Method for Inducing a Sustained Immune Response

ABSTRACT

A method for inducing a sustained immune response in humans or animal patient suffering from human immunodeficiency virus (HIV) acquired immune deficiency syndrome (AIDS, autoimmune disease, cancer, inflammation, and neurodegenerative diseases comprises daily administration to such patients a single oral tablet, rapidly dissolving film, capsule, liquid or cream dose of an Immediate release naltrexone composition comprising between about 0.01 to about 10 mg of naltrexone. In order to provide a benefit the naltrexone must be an Immediate release composition comprising between about 0.01 and about 10 mg of naltrexone

CROSS-REFERENCE To RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/437,365, filed Feb. 20, 2017 which claims priority under 35 U.S.C. §119(e) to Provisional U.S. Patent Application Ser. No. 62/296,759, filedFeb. 18, 2016. The disclosure of the aforementioned applications isincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods of inducing a sustained immuneresponse in patients suffering from human immunodeficiency virus (HIV)acquired immune deficiency syndrome (AIDS), autoimmune disease, cancer,inflammation, and neurodegenerative diseases comprising administering arapidly dissolving film, single oral tablet, capsule, liquid or creamdose of an Immediate release naltrexone composition comprising betweenabout 0.01 to about 10 mg of naltrexone.

BACKGROUND

Immediate release naltrexone composition comprising between about 0.01and about 10 mg of naltrexone was specifically designed to enhanceimmunomodulation and anticancer properties with fewer side effects thenexisting therapies. Clinical Studies have shown that to have animmunomodulating effect naltreoxone must be in an Immediate releaseformulation and not as timed release or slow release. The Immediaterelease naltrexone composition comprising between about 0.01 and about10 mg of naltrexone not only inhibit angiogenesis, but also induceapoptosis and growth arrest in resistant cancer cells. They also preventthe adhesion of cancer cells to bone marrow stromal cells and therebyinhibit the enhanced secretion of migratory factors, such as interleukin(IL)-6, TNF-α, and vascular endothelial growth factor.

Where high dose naltrexone and slow release naltrexone between 0.01 mgand 10 mg and an Immediate release naltrexone composition comprisesbetween about 0.01 mg and about 10 mg of naltrexone share commonality incategories of genes and are considered the same drug, the difference indosing and delivery method of the Immediate release naltrexone of theinvention produces a difference in the overall response of the immunesystem.

For a wide range of drugs, oral dosage forms such as tablets are clearlythe preferred form of delivery. This is due to a high level of patientacceptability and compliance (because they provide an accurate dosageand are easy to administer) as well as advantageous characteristicsduring and after manufacture, such as they typically show satisfactoryphysical and chemical stability, are convenient for packing, shippingand administering and offer advantages in manufacturing speed and cost.

However, oral dosage forms need carefully designed disintegrationcharacteristics to achieve the desired bioavailability for theincorporated drug, i.e. dissolution must precede absorption, in case ofimmediate release tablets should disintegrate rapidly after ingestion inorder to facilitate dissolution of the drug. Moreover, the drug loadingof conventional tablet formulations is often limited due to potentialgastrointestinal irritation (caused by locally high concentration)and/or patient compliance (which limits size and shape to achieve easyswallowing). The Naltrexone formulation described which comprisesbetween 0.05 mg and 10 mg requires immediate onset of action. To meetthis requirement immediate release dosage forms have been formulated todisintegrate rapidly after administration with enhanced rate ofdissolution.

To accomplish this goal tablets were developed using superdisintegrantssuch as cross linked polyvinylpyrrolidone or crospovidone(Polyplasdone), modified starches such as sodium starch glycolate (e.g.Primogel, Explotab), soy polysaccharides, cross linked alginic acid,gellan gum, xanthan gum, calcium silicates, ion exchange resins such asINDION 414 and modified celluloses such as carboxymethylcellulose(Croscarmellose sodium). These superdisintegrants provide instantaneousdisintegration of tablet after administration in stomach. In the case ofimmediate release liquid dosage forms and parenteral dosage forms thenaltrexone formulation described can be a suspension with typicaldispersion agents such as hydroxypropyl methylcellulose and AOT(dioctylsulfosuccinate).

Immediate release tablets are those which disintegrate rapidly anddissolve to release the medicaments. Immediate release may be providedfor by way of an appropriate pharmaceutically acceptable diluent orcarrier, which diluent or carrier does not prolong, to an appreciableextent, the rate of drug release and/or absorption. An Immediate releaseformulation excludes formulations which are adapted to provide for“modified”, “controlled”, “sustained”, “prolonged”, “extended” or“delayed” release of drug. The immediate-release tablets and capsulesrelease the active ingredient within a small period of time, typicallyless than 30 minutes.

There is a difference in the cell patterns of genes that are altered bythe treatment of Immediate release naltrexone of the invention versushigh dose naltrexone and slow release low dose naltrexone between 0.01mg and 10 mg. The differences are important because an Immediate releasenaltrexone composition which comprises between about 0.01 and about 10mg of naltrexone acts as an immunomodulator. Since the Immediate releasenaltrexone described blocks the opiate receptors only for a few hoursbefore it is naturally excreted, what results is a rebound effect; inwhich both the production and utilization of met (5) enkelphine opiategrowth factor are increased. Once the Immediate release naltrexone hasbeen metabolized, the elevated endorphins produced as a result of therebound effect can now interact with the more-sensitive andmore-plentiful receptors and assist in regulating cell growth andimmunity. This rebound effect is not observed with either high dosenaltrexone or slow release naltrexone. It is the reboundimmunomodulatory effect that effects the treatment of treating patientssuffering from human immunodeficiency virus (HIV) acquired immunedeficiency syndrome (AIDS), Autoimmune Disease, OpportunisticInfections, Cancer, Inflammation, and Neurodegenerative Diseases(“Younger J, Clin. Rheumatol. 2014; 33(4): 451-459. PMCID).

The immune system protects the body against infectious agents, includingbacteria, viruses, fungi, and parasites. In addition, the immune systemprotects against cancer, as well as disease states that result fromimmune imbalances and opportunistic infections. Stimulation of theimmune system by pharmaceuticals is an important approach to theprevention and treatment of diseases associated with immune suppressedstates.

The response by the immune system to an immunogen may be depressed as aconsequence of certain diseases or pathological conditions. For example,patients infected with the human immunodeficiency virus (HIV-1) maydevelop acquired immune deficiency syndrome (AIDS) or AIDS relatedcomplex (ARC), and thus have depressed immune responses. In addition topatients with HIV/AIDS patients undergoing cancer therapy, sufferingfrom opportunistic infection or inflammatory diseases have a depressedimmune system either due to the diseases or caused by theimmunosuppressing drug used in the treatment of cancer, autoimmunedisease and HIV/AIDS.

Patients with depressed immune systems are more susceptible topathological infections or malignancies against which a normal immunesystem would have otherwise provided sufficient protection. Other suchimmunocompromised individuals include patients with opportunisticinfections, autoimmune diseases, cancer, or undergoing X-rays, radiationtreatment, surgery, or chemotherapy treatment.

Current treatments used to prevent the development of immunodeficiencyin individuals with viral infections, HIV for example, usually involveadministration of compounds that inhibit viral DNA synthesis therebyslowing onset of viral-related immunosuppression.

More recent treatments against HIV include administration of proteaseinhibitors such as saquinovir, nefinavir, ritonavir and indinavir.Cytokine therapy is also used in the treatment of AIDS patients, withresearch groups having demonstrated efficacy of interleukin-2 (IL2) inelevating the CD4 T-cell subset in HIV positive patients (Kovacs, etal., N. Engl. J. Med., 1996; 335: 1350-1356). Reports have detailed thatIL2 can also increase CD8 T-cell count (Schmitz, et al., Science, 1999;283: 857-860). Unfortunately, the use of IL2 is normally accompanied bymajor toxicity (Davey, et al., JAMA, 2000; 284: 183-189). Many of thesesame drugs are used to treat cancer, autoimmune disease andneurodegenerative diseases.

Nevertheless, given the potential promise of these therapies directedtoward anti-retroviral effects, none have proven to be totally effectivein treating or preventing development of AIDS. In addition, many ofthese compounds cause adverse side effects including “black box”warnings of the risk of hematological, toxicity, myopathy, lacticacidosis hepatic decompensating, lactic acidosis, severe hepatomegalywith steatosis and exacerbation of hepatitis B, Drug interaction leadingto serious and life threating reactions, including sedative hypnotics,etc; hepatic metabolism, skin reactions low platelet count, diarrhea,nausea, renal toxicity, and bone marrow cytopenia. Numerous clinicalstudies with low dose naltrexone in normal volunteers, HIV positive,multiple sclerosis, autism, fibromyalgia, diabetes, and cancer patientsshowed no major toxicity.

Current treatments used to prevent the development of immunodeficiencyin individuals with autoimmune disease, Crohn's Disease, multiplesclerosis and cancer, for example, usually involve administration ofcompounds that slow or suppress the immune system response in an attemptto stop the inflammation involved in the autoimmune attack are calledimmunosuppressive medications. These drugs include corticosteroids(prednisone), methotrexate, cyclophosphamide, azathioprine, andcyclosporin. Unfortunately, these medications also suppress the abilityof the immune system to fight infection and have other potentiallyserious side effects.

More recent treatments against autoimmune diseases and cancer includeadministration of glucocorticoids, cytostatics are nitrogen mustards(cyclophosphamide), nitrosoureas, platinum compounds, interferons andTNF binding proteins.

Nevertheless, given the potential promise of these therapies directedtoward autoimmune disease and cancer, none have proven to be totallyeffective in treating or preventing development of autoimmune disease orcancer. In addition, many of these compounds cause adverse side effectsincluding “black box” warnings of the risk of hematological, toxicity,myopathy, lactic acidosis hepatic decompensating, lactic acidosis,severe hepatomegaly with steatosis and exacerbation of hepatitis B, Druginteraction leading to serious and life threating reactions, includingsedative hypnotics, etc; hepatic metabolism, skin reactions low plateletcount, diarrhea, nausea, renal toxicity, and bone marrow cytopenia.Numerous clinical studies with Immediate release naltrexone dosedbetween 0.01 mg and 10 mg in normal volunteers, HIV positive, multiplesclerosis, autism, fibromyalgia, diabetes, and cancer patients showed nomajor toxicity.

Thus, there exists a need in the art for improved methods of stimulatinga sustained immune system response in patients in need of suchtreatment, such as patients include those with compromised immune systemresponses (e.g. the potential to develop compromised immune systemresponses HIV-infected (e.g. AIDS patients), opportunistic infections,autoimmune disease, cancer, cardio vascular disease, inflammatorydiseases, and neurodegenerative diseases.

It is therefore unexpected that an Immediate release naltrexonecomposition comprising between about 0.01 mg and about 10 mg ofnaltrexone could be used in methods of treatment useful in producing asustained immune response in a patient comprising administering theactive agents on dosage schedule to a patient in need of such treatment.

It is also surprising that an Immediate release naltrexone compositioncomprising between about 0.01 mg and about 10 mg of naltrexone iseffective in promoting a sustained cell increase in immune systemresponse including sustained cell levels.

The present invention provides for, inter alia, methods of treatmentuseful for inducing a sustained immune system response in animmunocompromised patient in need of such treatment wherein the methodcomprises administering to the patient an Immediate release naltrexonecomposition comprising between about 0.01 mg and about 10 mg ofnaltrexone, either alone, combined, or in further combination with othercompounds useful for increasing immune system response, includingvaccines. In this context, “immunocompromised” refers to any reductionin T-cell number or function.

The present invention also provides for, inter alia, methods oftreatment useful for inducing a sustained immune system response in anHIV-infected patient, wherein the method comprises administering to theHIV-infected patient an Immediate release naltrexone compositioncomprising between about 0.01 mg and about 10 mg of naltrexone, eitheralone, combined, or in further combination with other compounds usefulfor slowing the progression of HIV proliferation or HIV-associatedinfections, such as abacavir, didanosine, emtricitabine, lamivudine,stavudine, tenofovir disoproxil fumarate, zidovudine (AZT), atazanivir,darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir,tipranavir, enfuviritide, maraviroc, dolutegravir, elvitegravir,raltegravir, cobicistat, efavirenz, nevirapine, etravirine andrilpivine. Combination HIV therapies are also included to beadministered with the naltrexone formulation described such as abacavirand lamivudine; abacavir, dolutegravir and lamivudine; abacavirlamivudine and zidovudine; atazanavir and cobicistat; darunavir andcobicistat; efavirenz, emtricitabine and tenofovir disoproxil fumerate;elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide fumerate;elvitegravir, cobicistat, emtricitabine and tenofovir disoproxilfumerate; emtricitabine, rilpivirine and tenofovir alafenamide;emtricitabine, rilpivirine and tenofovir disoproxil fumerate;emtricitabine and tenofovir alafenamide; emtricitabine and tenofovirdisoproxil fumerate; lamivudine and zidovudine; and lopinavir andritonavir. Additionally, cytokines such as G-CSF, IL-11, IL-12, IL-2;and gamma interferon and antibiotics or other drugs used for thetreatment or prevention of infections in HIV-infected patients.Administration to such patients comprises a single oral, liquid or creamdose of an Immediate release naltrexone composition comprising betweenabout 0.01 mg to about 10 mg of naltrexone. It is known that fornaltrexone blocks the opiate receptor, but the effect on the immunesystem only occurs when the opiate receptor is blocked for a shortperiod of time which requires the naltrexone be an Immediate releasenaltrexone composition comprising between about 0.01 mg and about 10 mgof naltrexone to have an immunomodulatory effect.

The Immediate release naltrexone composition comprising between about0.01 mg and about 10 mg of naltrexone was specifically designed toenhance immunomodulation and anticancer properties but with less sideeffects. (Mohammad A. Seifrabiei, Mohammad Abbasi, Ali Montazeri,Fatemeh Shahnazari and Arash Pooya American Journal of Applied Sciences5 (7): 872-875, 2008.)

Clinical Studies reveal that an Immediate release naltrexone compositioncomprising between about 0.01 and about 10 mg of naltrexone not onlyinhibit angiogenesis but also induce apoptosis and growth arrest inresistant cancer cells. They also prevent the adhesion of cancer cellsto bone marrow stromal cells and thereby inhibit the enhanced secretionof migratory factors, such as interleukin (IL)-6, TNF-α, and vascularendothelial growth factor. In research experiments, ovarian cancer cellswere treated with either water as the control or different dosingregimens of naltrexone to replicate high dose versus Immediate releasedosing of naltrexone. Using the Immediate release low or short-termdosing composition of naltrexone it was observed that the growth ofcancer cells was slowed; however, when a high dose of naltrexone wasused, cancer cells were stimulated and grew faster.

Autoimmune disease, cancer, cardiovascular disease, inflammatory boweldisease, Musculo-skeletal disorders, metabolic disorders and neurodegenerative diseases develop when the immune system begins todysfunction which can be caused by a number of factors. When an organismmounts an anti-self response, usually as a result of abnormalities ofthe afferent parts of the immune system which are involved inantigen-specific responses and chronic inflammation which can be can betriggered by cellular stress and dysfunction, such as that caused byexcessive calorie consumption, environmental factors, elevated bloodsugar levels, and oxidative stress. It is now clear that the destructivecapacity of chronic inflammation is unprecedented among physiologicprocesses (Karin et al. 2006). Chronic inflammation is caused by acausative agent, non-degradable pathogens that cause persistentinflammation, infection with some types of viruses, persistent foreignbodies, overactive immune system reactions and it causes major cellsinvolvement—macrophages, lymphocytes, plasma cells (these three aremononuclear cells), and fibroblast with primary mediators—reactiveoxygen species, hydrolytic enzymes, IFN-γ and other cytokines, growthfactor and long term inflammation causes the destruction of tissue,thickening and scarring of connective tissue (fibrosis), death of cellsor tissues (necrosis).

Naltrexone when used in Immediate releasing composition comprisingbetween about 0.01 mg to about 10 mg of naltrexone is animmune-modulating drug and as such has more then one mechanism of actionin the treatment of immune deficiency diseases, opportunisticinfections, autoimmune disease, cancer, cardio vascular disease, chronicinfections, inflammatory diseases, inflammatory bowel disease,musculo-skeletal disorders, metabolic disorders and neurodegenerativediseases. As an immune-modulating drug, naltrexone has a cascade benefiteffect on the immune system.

As an immunomodulatory drug, Immediate release naltrexone comprisingbetween about 0.01 mg and about 10 mg of naltrexone works by binding fora short period of time with mu receptors. An Immediate releasenaltrexone composition comprising between about 0.01 mg and about 10 mghas an affinity to at least a million extremely specific deltareceptors. An Immediate release naltrexone composition comprisingbetween about 0.01 mg and about 10 mg of naltrexone has only a weakbinding to only one hundred such receptors. An Immediate releasenaltrexone composition comprising between about 0.01 mg and about 10 mgof naltrexone blocks the mu receptor and upregulates delta receptors sothe endorphins released at night binds to the delta not the mureceptors, which results in stimulation of the immune system via deltareceptors and the blocking of the mu agonists for longer then 4 to 6hours suppress the immune system.

The blocking of the mu receptor for a short period causes an increasethe products of cytokines including met-enkelphine. This interactionregulates normal cell growth. If too much met-enkelphine or opiategrowth fact (“OGF”) OGF is released, it slows cell growth and if toolittle OGF or enkephalin is released the cells proliferate in an out ofcontrol manner and have the potential to become cancer cells oroveractive immune cells. If the naltrexone dose is too high, or anImmediate release dose composition comprising an amount of naltrexonehigher than about 10 mg of naltrexone, then naltrexone is still bound tothe opioid receptor and the met-enkephalin cannot interact with thereceptor. The end result and risk of taking such compositions is thateither there will be no effect or the cancer cell growth

High dose naltrexone, slow release low dose naltrexone and Immediaterelease naltrexone compositions comprising between about 0.01 and about10 mg of naltrexone share commonality in categories of genes and areconsidered same drug except for the difference between both the type ofdelivery and the dose. These factors determine if naltrexone acts as aimmunomodulator and is a benefit to immune comprised patients.

An Immediate release naltrexone composition comprising between about0.01 mg and about 10 mg of naltrexone blocks opiate receptorstemporarily (typically 2-4 hours), which leads to rebound increase inendogenous opioids and endorphins but especially in the production ofcytokines which are critical to immune health. (“Critical Regulators ofCytokine Signaling and Immune Responses”, International Congress SeriesVolume 1285, November 2005, Pages 121-129)

An Immediate Release naltrexone composition comprising between about0.01 mg and about 10 mg: increases endorphins and inhibits cellproliferation in vivo, while high dose naltrexone or slow releasenaltrexone decreases endorphins, promotes cell growth, Increasesendorphin levels, decreased inflammatory cytokines, shift from Th1(pro-inflammatory) to Th2 (anti-inflammatory), reduces production of TNFand begins to effect TRL4 and TRL9 within 72 hours and reduceinflammation. (Faith; Robert E.; Faith, Robert E.; Murgo, Anthony J.;Good, Robert A.; Plotnikoff, Nicholas P. Cytokines: Stress and Immunity,Second Edition (Page 362).).

Parallel with OGFR function, as OGF exhibits cancer growth featuressimilar to an Immediate release naltrexone composition comprisingbetween about 0.01 mg and about 10 mg. But continuous 48 h exposure tonaltrexone has no dramatic effect in a number of tumors, no effect onpancreatic cancer cells: MIA-PaCa2, PANC1, and BxPC3, no effect onglioma cells: T98G and U87MG, no effect on A549 (lung) and HCT116 (CRC)no effect expression of CDK Inhibitors p15, p18, p19, and p27 are notaltered by Immediate release naltrexone.

Continuous exposure naltrexone in a dose between 0.01 mg and 10 mgstimulates the growth of tumors. Treatment with an Immediate releasenaltrexone composition comprising between about 0.01 mg and about 10 mgof naltrexone inhibit tumor growth, this is associated with theshort-term blockade of opioid receptors. This blockade causes acompensatory increase in receptors; however, the result of this differswith dose. An Immediate release naltrexone composition comprisingbetween about 0.01 mg and about 10 mg of naltrexone is associated withcell cycle responses via OGF action on p16^(INK4a) andp21^(WAF1/CIP)p16.

The continuous exposure to an Immediate release naltrexone compositioncomprising between about 0.01 mg and about 10 mg of naltrexone has adramatic effect in the number of tumors such as pancreatic cancer cells,glioma cells, TRL9, TRL4, and T-cell productions and beta-endorphinlevels. The effect on beta-endorphin levels is very important becausebeta-endorphin levels are reduced to ⅛ to ¼ normal levels in autoimmunerelated and rheumatic disease as Fibromyalgia, MS, Crohn's Disease,endometriosis, cluster headaches, chronic migraines, lupus, arthritisand gout. An Immediate release naltrexone composition comprising betweenabout 0.01 mg and about 10 mg has been shown to increasebeta-endorphines levels, which shifts the balance from Th1 to Th2 cellsto decrease inflammation.

Like opiate receptors toll like receptors are present throughout thebody. They are part of the bodies first line defense mechanism againstinvading pathogens (such as viruses, parasites, bacteria, protozoaeetc.). Basically, these receptors spot “non-human” proteins and start adefense against them. We found that not all the cytokine expressions bythe macrophage were decreased while TLR9 was downregulated, IL-12,TNF-alpha, IFN-gamma and IL-1beta expressions were significantlydecreased, but IL-6, IFN-beta and IL-10 expressions were not affected.Interestingly, the level of IFN-alpha was even increased. Thisalteration of cytokines produced by TLR9-downregulated APCs upon CpG ODNstimulation might indicate that the role of CpG DNA is more complicatedin the pathogenesis and prevention of diseases. In addition, LR2 andTLR9 and co-stimulation of TLRs have been shown to induce HIVreplication. Together these results underscore the importance of TLRs inbacterial Ag- and CpG DNA-induced HIV-LTR trans-activation and HIVreplication. These observations may be important in understanding therole of the innate immune system and the molecular mechanisms involvedin the increased HIV replication and HIV disease progression associatedwith multiple opportunistic infections. Based on the present evidence,it is likely that TRL9-activated immune responses to the CpG motif inGEM91 were responsible for the observed increases in viral load, andthat CpG motif in oligonucleotide phosphorothioates is biologicallyactive. (J Immunol. 2003 May 15; 170(10):5159-64.) Toll-like receptor 2(TLR2) and TLR9 signaling results in HIV-long terminal repeattrans-activation and HIV replication in HIV-1 transgenic mouse spleencells: implications of simultaneous activation of TLRs on HIVreplication.) This supports the premise that low dose naltrexone isuseful in the treatment of HIV/AIDS. The connection between an Immediaterelease naltrexone composition comprising between about 0.01 mg andabout 10 mg of naltrexone as effective the regulations of TRL9 in thestopping of the progression of HIV/AIDS and opportunistic infections hasnot been previously described. (Plotnikoff N P, Wybran J:Methionine-enkephalin Shows Promise in Reducing HIV in Blood. Ann N YAcad Sci. 1987; 496:108-14.)

It is thought that many autoimmune diseases are caused by feedbackloops. For example, chronic infection can cause huge inflammatoryresponse (such as Epstein Barr, Crohn's Disease, IBS, fibromyalgia) andthe excess inflammatory response damages cells in the body in the effortto kill the infection.

During this process, the TLR-4 receptors are constantly being stimulatedto fight off an infection, which does not exist, because the TLR-4receptors are being stimulated all the time by natural parts of yourblood. This, unfortunately, leads to the body ignoring real infectionsand the body being induced to attack healthy cells which results in thebroad spectrum of autoimmune diseases.

An Immediate release naltrexone composition comprising between about0.01 mg and about 10 mg reduces nitric oxide synthase activity, inhibitsglutamate formation and microglial activity, and reduces proinflammatorycytokine and neurotoxic superoxide production. Filamin A modulates themu opioid receptor. An Immediate release naltrexone compositioncomprising between about 0.01 mg and about 10 mg effect adenosinereceptors involved in pain signaling and intrathecal adenosinesuppresses pain.

It is via the non-opioid antagonist path that an Immediate releasenaltrexone composition comprising between about 0.01 and about 10 mg ofnaltrexone exerts its anti-inflammatory effects. Microglia are centralnervous system immune cells that are activated by a wide range oftriggers. Once activated, microglia produce inflammatory and excitatoryfactors that can cause such as pain sensitivity, fatigue, cognitivedisruption, sleep disorders, mood disorders, and general malaise.

When chronically activated, the resulting pro-inflammatory cascade maybecome neurotoxic, causing several deleterious effects. Given the widevariety of diseases that are caused by increase inflammatory factorsproduced by activated microglia (e.g., pro-inflammatory cytokines,substance P, nitric oxide, and excitatory amino acids) a range ofsymptoms and medical outcomes could share the pathophysiologicalmechanism of central inflammation. Conditions such as fibromyalgia mayinvolve chronic glial cell activation and subsequent production ofpro-inflammatory factors.

The hypothesis is indirectly and partially supported by the high degreeof symptomatic overlap between fibromyalgia and cytokine-inducedillness. An Immediate release naltrexone composition comprising betweenabout 0.01 and about 10 mg of naltrexone blocks the TLR-4 receptorexperimentally, and in vivo. (In a test tube and also humans) Blockingthese receptors causes the whole cycle to activate or re-balance and theimmune system gradually return too normal. (Faith, R E, Murgo, A J, GoodR A, Plotnikoff N P, 2012 Cytokines: Stress and Immunity, SecondEdition).

Unfortunately, the TLR-4 receptors probably cannot “unlearn” to react tosomething, so the treatment with low dose naltrexone is long term andwill control the symptoms after varying periods of initial treatment,depending on which set of TLR-4 receptors are malfunctioning.

Crohn's patients have positive response due to the number of TLR-4 andTRL-9 receptors in the bowel and intestines. Studies have shown whenpatients stopped taking an Immediate release naltrexone compositioncomprising between about 0.01 and about 10 mg of naltrexone have seenthe return of the chronic disease and symptoms and when patients resumetreatment with an Immediate release naltrexone composition comprisingbetween about 0.01 and about 10 mg the symptoms subside once again.

The central nervous system (CNS) is made up of nerves and glial cells.The function of the glia is to provide immune protection and providedefense to the CNS. Under normal conditions the glia remain in aninactivate state. They become activated readily in response to infectionor injury. The most important change that happens during inflammation ofthe brain and spinal cord (CNS) is activation of glial cells, whichexplains the effectiveness of an Immediate release naltrexonecomposition comprising between about 0.01 and about 10 mg of naltrexonehelps with neurodegenerative diseases.

When glial cells are activated they trigger the release of certainchemicals known as pro-inflammatory and neurotoxic factors. Thesefactors include several cytokines such as tumor necrosis factor alpha(TNF-α) and interleukin one beta (IL1-β), fatty acid metabolites andfree radicals such as nitric oxide and superoxide. In painful conditionssuch as complex regional pain and fibromyalgia and neuropathic pain,damage to the peripheral nerves shifts the glial cells to an activatedstate within the spinal cord.

The glial cells are made up of microglia and astrocytes. The microgliaguard and protect the immune system and the astrocytes help maintaincell fluid balance which is important for the action of chemicals in thecells called neurotransmitters (needed to control nerve function). Glialcells are activated by trauma, surgery, injury, infection, and opioids.When activated, glial release pro-inflammatory and neurotoxic factors(cytokines). Opiate antagonists that block the effects of opioids andhave been shown to help prevent activation of glial cells. Low dosenaltrexone has been shown to inhibit the activation of glial cells.(Younger, J et al. Arthritis Rheum. 2013; 65 (2): 529-538)

Immediate release naltrexone has been shown to effect telomeres.Telomeres are inside the nucleus of a cell, our genes are arranged alongtwisted, double-stranded molecules of DNA called chromosomes. At theends of the chromosomes are stretches of DNA called telomeres, whichprotect our genetic data, make it possible for cells to divide, and havebeen implicated in how we age and get cancer.

Telomeres have been compared with the plastic tips on shoelaces, becausethey keep chromosome ends from fraying and sticking to each other, whichwould destroy or scramble an organism's genetic information.

Yet, each time a cell divides, the telomeres get shorter. When telomeresget too short, the cell can no longer divide; it becomes inactive or“senescent” or it dies. This shortening process is associated withaging, cancer, and a higher risk of death.

Clinical studies have shown that telomeres are reduced in human livertissues with age and chronic inflammation. (Telomere Reduction in HumanLiver Tissues with Age and Chronic Inflammation experimental cellresearch 256(2):578-582 ⋅ April 2000). Immediate release naltrexone is aproven immunomodulator that helps to reset and rebalance balance of theimmune system between the cellular (Th1) and the humoral (Th2) immunesystems. Immune balance is regulated through T-helper cells that producecytokines. The Th1 lymphocytes help fight pathogens that are withincells such as viruses and among cells such as cancer through activationof interferon-gamma and macrophages. The Th2 lymphocytes target externalpathogens like parasites, allergens, toxins through the activation ofB-cells and antibody production therefore reducing chronic inflammation.Immediate release low dose naltrexone has been shown to regulatecytokines causing the modulation of TGF-B, leading to a reduction ofTh-17, the promoter of autoimmunity. Low dose naltrexone turns off thecells growth that causes autoimmune dysfunction. Findings demonstratethat cancer cell lines that express functional TLR4 and TLR9 withpossible effects on cancer progression and outcome of BCG-based(“Immunotherapy. J Biol Chem. 2013 Nov. 15; 288(46):33171-80. doi: 10.1074/jbc.M113.518175. Epub 2013 Oct. 4. Inhibition of TelomeraseRecruitment and Cancer Cell Death. Nakashima M, Nandakumar J, Sullivan KD, Espinosa J M, Cech TR”).

An Immediate release naltrexone composition comprising between about0.01 mg and about 10 mg of naltrexone has been shown in inflammatorybowel disease to halt inflammation due to the shift of Th1 to TH2 whichthen allow the telomeres to lengthen but at the same time Immediaterelease naltrexone composition will inhibit growth causing the telomerestoo shorten and when the cells can no longer divide; they die. Thisshortening process is associated with aging, cancer, and a higher riskof death.

Research into the lengthening of telomeres to reduce inflammationindicates that telomeres lengthen in all cells including cancer cells.Immediate release naltrexone is an immunomodulator and when administeredin an Immediate release composition comprising between about 0.01 mg andabout 10 mg of naltrexone it will lengthen telomeres in cells andtherefore reduce inflammation in patients as shown in Crohn's andinflammatory bowel disease patients. Low dose naltrexone is a proven toinhibit cells growth in cancer cells, and could assist in the slowingdown of cell death and turn back the aging process by lengtheningtelomeres. (Telomere Extension Turns Back Aging Clock in Cultured HumanCells, Jan. 23, 2015 Stanford University Medical Center. Ramunas, E.Yakubov, J. J. Brady, S. Y. Corbel, C. Holbrook, M Brandt, J. Stein, J.G. Santiago, J. P. Cooke, H. M Blau.

The majority of the currently practiced drug treatments for autoimmunedisease, cancer, cardio vascular disease, inflammatory diseases,inflammatory bowel disease, musculo-skeletal disorders, metabolicdisorders and neuro degenerative diseases have significant drawbacks.The number of patients taking immunosuppressive drugs for the managementof autoimmune inflammatory conditions is increasing. The generalpractitioner needs to be active in preventing, monitoring and managingthe adverse effects of these drugs even long after the treatment hasceased. Monitoring is required because immunosuppressive drugs increasethe risks of infection, malignancy, cardiovascular disease and bonemarrow suppression. Apart from gastrointestinal disturbances, thenonsteroidal anti-inflammatory drugs have been shown to cause renaltoxicity and therefore must be avoided particularly in lupus patientswith renal involvement.

The antimalarial may cause serious retinopathy, which can occur severalyears after initiation of therapy. Chronic glucocorticoid therapy isassociated with a number of pernicious side effects, includinghypertension, excessive immunosuppression and CNS dysfunction.Immunosuppressive and cytotoxic agent a primary cause or secondarycontributor in many cause bone marrow depression and lead to seriousdiseases, usually as a result of the formation of autoantibodies by theimmune system of the organisms, which attack its own cells. Suchdiseases include, for example, systemic lupus erythematosus, rheumatoidarthritis, autoimmune thyroiditis, autoimmune hemolytic anemia, andcertain forms of progressive liver disease. Low dose naltrexone has beenshown to increase bone marrow.

Rheumatoid arthritis in its fully developed form is a symmetrical,inflammatory disease of the synovial lining of peripheral joints, whichleads to destructive changes. Although arthritis is the most frequentand prominent manifestation, this is a generalized disease involvingmany body systems. Pathologically, rheumatoid arthritis is aninflammatory disease involving the immune system. Immune complexes(antigen/antibody) form within the joint and activate the complementsystem. White blood cells are then attracted into the synovial fluid.These cells phagocytose the immune complexes and in so doing releaselysosomal enzymes and other chemical mediators of inflammation.Continued inflammation causes the synovium to proliferate and spreadover the joint surface. The thickened synovial tissue, called pannus,releases enzymes, which erode both cartilage and bone to cause permanentdamage.

Rheumatoid arthritis is treated with many of the same pharmaceuticalagents used in systemic lupus. Most patients initially receivenonsteroidal anti-inflammatory drugs, sometimes together otheranalgesics. Where the disease is not adequately controlled with theseagents, disease-modifying antirheumatic drugs, such, D-penicillamine, aswell as steroids and biologic agents. Continuing therapy with any or allof the aforementioned categories of drugs can produce a variety ofwell-known adverse effects, and none of these drugs are significantlyeffective in achieving true remission of the disease in most patients.

It is known that inflammatory cells such as polymorphonuclear leukocyteshave opiate receptors. The endogenous opioid, endorphin has been shownin both animal and human studies to stimulate superoxide radicalproduction by human polymorphonuclear leukocytes via an opiate receptor.This superoxide production has been shown to be stopped by equimolarconcentrations of the opiate antagonist naloxone. (B. M. Sharp et al.,J. Pharm. Exp. Ther., 242(2):579-582, 1987).

As used herein, the term human immunodeficiency virus, cancer, cardiovascular disease, inflammatory diseases, inflammatory bowel disease,Musculo-skeletal disorders, metabolic disorders and neuro degenerativediseases refers the daily administration of a low dose naltrexonecomposition comprising between about 0.01 and about 10 mg of naltrexonehas been shown to any disease state or condition associated with theshortening of telomerase causing cell death chronic inflammation andimmune dysfunction.

SUMMARY OF THE INVENTION

It is the object of the present invention to provide a method forinducing sustained immune response in humans or animal patient sufferingfrom human immunodeficiency virus (HIV) acquired immune deficiencysyndrome (AIDS, autoimmune disease, cancer, inflammation, andneurodegenerative diseases which avoids the drawbacks and disadvantagesof prior art and present standard of care drug treatment methods whileachieving dramatic symptomatic relief and reducing inflammation levels,systemic autoantibody levels increase production of increasingproliferation and functional activities of CD4+T-cells and CD8+T-cellswhich will play a role in anti-virus and anti-tumor activities;increasing maturation of dendritic cells which will initiate andintensify T-cell responses; increasing secretion of cytokines such asIL-2, TNF, IL-12 and IFN-≡ which will amplify the T-cell response andmediate interaction among immune cells, including the non-opiatereceptors like TRL-4 and TRL-9 through forming a modulated and balancedimmunity between Th1 and Th2; increasing functions of macrophages,resulting in enhanced cellular immunity through secreting a set ofcytokines; and increasing activity of NK cells which have the ability tokill cancer cells and virus-infected cells and lengthen telomers therebyslowing cell death. In cancer, an Immediate release naltrexonecomposition comprising between about 0.01 and about 10 mg of naltrexoneenhances maturation of bone marrow dendritic cells “(BMDCs) Meng J, MengY, Plotnikoff N P, Youkilis G, Griffin N, Shan F.—Low dose naltrexoneenhances maturation of bone marrow dendritic cells (BMDCs). IntImmunopharmacol. 2013 December; 17(4):1084”) which is important whenpatients are undergoing any immunosupression therapy as low dosenaltrexone can held offset the toxic side effects of these treatments.

The differences between naltrexone at higher than about 11 mg to 300 mgand naltrexone between 0.01 and 10 mg slow release and Immediate releasebetween 1 mg and 10 mg have not been previously recognized. Thesurprising characteristics of Immediate release naltrexone between 0.01mg and 10 mg such as its effect on telomeres and increase production ofincreasing proliferation and functional activities of CD4+T-cells andCD8+T-cells which play a role in anti-virus and anti-tumor activities;increasing maturation of dendritic cells which will initiate andintensify T-cell responses; increasing secretion of cytokines such asIL-2, TNF, IL-12 and IFN-γ which will amplify the T-cell response andmediate interaction among immune cells, including TRL-4 and TRL-9forming a modulated and balanced immunity; increasing functions ofmacrophages, resulting in enhanced cellular immunity through secreting aset of cytokines; and increasing activity of NK cells which have theability to kill cancer cells, increase viral load, effect LR2 and TLR9to slow down the HIV replication and virus-infected cells, lengthentelomers slowing cell death.

The invention provides a method for treating or preventing viralinfections comprising administering to a mammal in need thereof anImmediate release pharmaceutical composition comprising between about0.01 mg and about 10.0 mg of naltrexone or a pharmaceutically acceptablesalt thereof alone or in combination with one or more anti-viral agents.The antiviral agent is selected from the group consisting of aninterferon, an immunomodulator, a viral replication inhibitor, anantisense agent, a therapeutic vaccine, a viral polymerase inhibitor, anucleoside inhibitor, a viral protease inhibitor, a viral helicaseinhibitor, a virion production inhibitor, a viral entry inhibitor, aviral assembly inhibitor, and an antibody therapy (monoclonal orpolyclonal).

The invention further provides that the viral infection is chosen fromthe group consisting of molluscum contagiosum infection, HTLV infection,HTLV-1 infection, hepatitis-A, HCV, HBV, HIV/AIDS infection, humanpapilloma virus infection, herpes virus infection, genital herpesinfection, viral dysentery, flu, measles, rubella, chickenpox, mumps,polio, rabies, mononucleosis, ebola, respiratory syncytial virus, denguefever, yellow fever, lassa fever, arena virus, bunyavirus, Filovirus,flavivirus, hantavirus, rotavirus, viral meningitis, west Nile fever,arbovirus, parainfluenza, smallpox, Epstein-Barr virus, denguehemorrhagic fever, cytomegalovirus, infant cytomegalic virus,progressive multifocal leukoencephalopathy, viral gastroenteritis, ahepatitis, cold sores, ocular herpes, meningitis, encephalitis,shingles, encephalitis, California serogroup viral, St. Louisencephalitis, rift valley fever, hand, foot, & mouth disease, hendravirus, enteroviruses, astrovirus, adenoviruses, Japanese encephalitis,lymphocytic choriomeningitis, roseola infantum, sandfly fever, SARS,warts, cat scratch disease, slap-cheek syndrome, orf, pityriasis roseaand lyssavirus. Preferably the viral infection to be treated orprevented is HIV/AIDS infection. the Preferably the additionalanti-viral agent is chosen from the group consisting of abacavir,didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxilfumarate, zidovudine (AZT), atazanivir, darunavir, fosamprenavir,indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, enfuviritide,maraviroc, dolutegravir, elvitegravir, raltegravir, cobicistat,efavirenz, nevirapine and etravirine or the combinations rilpivineabacavir and lamivudine; abacavir, dolutegravir and lamivudine; abacavirlamivudine and zidovudine; atazanavir and cobicistat; darunavir andcobicistat; efavirenz, emtricitabine and tenofovir disoproxil fumerate;elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide fumerate;elvitegravir, cobicistat, emtricitabine and tenofovir disoproxilfumerate; emtricitabine, rilpivirine and tenofovir alafenamide;emtricitabine, rilpivirine and tenofovir disoproxil fumerate;emtricitabine and tenofovir alafenamide; emtricitabine and tenofovirdisoproxil fumerate; lamivudine and zidovudine; and lopinavir andritonavir.

The invention further provides a method for treating or preventing viralinfections comprising administering to a mammal in need thereof anImmediate release pharmaceutical composition comprising between about0.01 mg and about 8.0 mg of naltrexone or a pharmaceutically acceptablesalt thereof.

The invention further provides a method for treating or preventing viralinfections comprising administering to a mammal in need thereof anImmediate release pharmaceutical composition comprising between about0.01 mg and about 6.0 mg of naltrexone or a pharmaceutically acceptablesalt thereof.

The invention further provides a method for treating or preventing viralinfections comprising administering to a mammal in need thereof anImmediate release pharmaceutical composition comprising between about0.01 mg and about 4.5 mg of naltrexone or a pharmaceutically acceptablesalt thereof.

The invention also provides for an administration is once in a 24 hourperiod.

The invention also provides that the mammal is a human.

The invention also provides that the pharmaceutically acceptable salt ofnaltrexone is the hydrochloride salt.

The invention also provides a method of treating or preventing viralinfection using an Immediate release composition which releases thepharmaceutically acceptable salt of naltrexone completely within about60 minutes.

The invention also provides that the administration route is chosen fromthe group consisting of oral, sublingual, subcutaneous, intramuscular,intravenous, topical, local, intratracheal, intranasal, transdermal andrectal administration.

The invention also provides a method of treating or preventing viralinfection using an Immediate release composition of naltrexone in theform of a rapidly dissolving film, capsules (including soft gel) ortablet.

The invention provides a method for treating or preventing cancercomprising administering to a mammal in need thereof an Immediaterelease pharmaceutical composition comprising between about 0.01 mg andabout 10.0 mg of naltrexone or a pharmaceutically acceptable saltthereof alone or in combination with one or more anti-cancer agents orradiation.

The invention further provides a method for treating cancer comprisingadministering to a mammal in need thereof an Immediate releasepharmaceutical composition comprising between about 0.01 mg and about8.0 mg of naltrexone or a pharmaceutically acceptable salt thereof.

The invention further provides a method for treating cancer comprisingadministering to a mammal in need thereof an Immediate releasepharmaceutical composition comprising between about 0.01 mg and about6.0 mg of naltrexone or a pharmaceutically acceptable salt thereof.

The invention further provides a method for treating cancer comprisingadministering to a mammal in need thereof an Immediate releasepharmaceutical composition comprising between about 0.01 mg and about4.5 mg of naltrexone or a pharmaceutically acceptable salt thereof.

The invention further provides a method of treating or preventing cancerwhere the cancer is chosen from the group consisting of malignanttumors, benign tumors, solid tumors, sarcomas, carcinomas,hyperproliferative disorders, carcinoids, Ewing sarcomas, Kaposisarcomas, brain tumors, tumors originating from the brain and/or thenervous system and/or the meninges, gliomas, glioblastomas,neuroblastomas, stomach cancer, kidney cancer, kidney cell carcinomas,prostate cancer, prostate carcinomas, connective tissue tumors, softtissue sarcomas, pancreas tumors, liver tumors, head tumors, necktumors, laryngeal cancer, esophageal cancer, thyroid cancer,osteosarcomas, retinoblastomas, thymoma, testicular cancer, lung cancer,lung adenocarcinoma, small cell lung carcinoma, bronchial carcinomas,breast cancer, intestinal cancer, colorectal tumors, colon carcinomas,rectum carcinomas, gynaecological tumors, ovary tumors/ovarian tumors,uterine cancer, cervical cancer, cervix carcinomas, cancer of body ofuterus, corpus carcinomas, endometrial carcinomas, urinary bladdercancer, urogenital tract cancer, bladder cancer, skin cancer, epithelialtumors, squamous epithelial carcinoma, basaliomas, spinaliomas,melanomas, intraocular melanomas, leukemias, monocyte leukemia, chronicleukemias, chronic myelotic leukemia, chronic lymphatic leukemia, acuteleukemias, acute myelotic leukemia, acute lymphatic leukemia andlymphomas.

The invention also provides for an administration is once in a 24 hourperiod.

The invention also provides that the mammal is a human.

The invention also provides that the pharmaceutically acceptable salt ofnaltrexone is the hydrochloride salt.

The invention also provides a method of treating cancer using anImmediate release composition which releases the pharmaceuticallyacceptable salt of naltrexone completely within about 60 minutes.

The invention also provides that the administration route is chosen fromthe group consisting of oral, sublingual, subcutaneous, intramuscular,intravenous, topical, local, intratracheal, intranasal, transdermal andrectal administration.

The invention also provides a method of treating cancer using anImmediate release composition of naltrexone in the form of a rapidlydissolving films, capsules (including soft gel) or tablet.

The invention further provides that the anti-cancer agents are chosenfrom the group consisting of genotoxic agents, mitotic poisons,anti-metabolites, proteasome inhibitors, kinase inhibitors andantibodies.

The invention further provides that the anti-cancer agents are chosenfrom the group consisting of abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenictrioxide, asparaginase, azacitidine, BCG Live, bevacuzimab,fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone,capecitabine, camptothecin, carboplatin, carmustine, celecoxib,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa,daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral),doxorubicin hydrochloride, dromostanolone propionate, epirubicin,epoetin alfa, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib,gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate,hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate,methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone,nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimersodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim,sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen,temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,zoledronate, and zoledronic acid.

The invention also provides a method for treating autoimmune andinflammatory diseases comprising administering to a mammal in needthereof an Immediate release pharmaceutical composition comprisingbetween about 0.01 mg and about 10.0 mg of naltrexone or apharmaceutically acceptable salt thereof.

The invention also provides a method for treating autoimmune andinflammatory diseases comprising administering to a mammal in needthereof an Immediate release pharmaceutical composition comprisingbetween about 0.01 mg and about 8.0 mg of naltrexone or apharmaceutically acceptable salt thereof.

The invention further provides a method for treating or preventingautoimmune and inflammatory diseases comprising administering to amammal in need thereof an Immediate release pharmaceutical compositioncomprising between about 0.01 mg and about 6.0 mg of naltrexone or apharmaceutically acceptable salt thereof.

The invention also provides a method for treating autoimmune andinflammatory diseases comprising administering to a mammal in needthereof between about 0.01 mg and about 4.5 mg of naltrexone or apharmaceutically acceptable salt thereof in an Immediate releaseformulation.

The invention also provides that the autoimmune and inflammatorydiseases are chosen from the group consisting of allergic diseases,amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus,chronic rheumatoid arthritis, type I diabetes mellitus, inflammatorybowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn'sdisease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,autoimmune myositis, Wegener's granulomatosis, ichthyosis, Gravesophthalmopathy and asthma, bone marrow or organ transplant rejection orgraft-versus-host disease, transplantation of organs or tissue,graft-versus-host diseases brought about by transplantation, Hashimoto'sthyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis,uveitis, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, post-infectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis, inflammatory andhyperproliferative skin diseases, psoriasis, atopic dermatitis, contactdermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichenplanus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria,angioedemas, vasculitis, erythema, cutaneous eosinophilia, acne,alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitisassociated with Behcet's disease, keratitis, herpetic keratitis, conicalcornea, dystrophia epithelialis comeae, corneal leukoma, ocularpemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy,Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversibleobstructive airway disease, chronic obstructive pulmonary disorder(COPD), bronchial asthma, allergic asthma, intrinsic asthma, extrinsicasthma, dust asthma, chronic or inveterate asthma, late asthma andairway hyper-responsiveness, bronchitis, gastric ulcers, vascular damagecaused by ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns, coeliac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerativecolitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy,multiple myositis, Guillain-Barre syndrome, Meniere's disease,polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenesis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, partial liver resection,acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock,or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic cirrhosis, hepatic failure, fulminant hepatic failure,late-onset hepatic failure, “acute-on-chronic” liver failure,augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMVinfection, AIDS, trauma, Blephartis, and chronic bacterial infection.

The invention also provides for administration once in a 24 hour period.

The invention also provides a method where the mammal is a human.

The invention also provides that the method uses the hydrochloride saltof naltrexone.

The invention also provides a method using an Immediate releasecomposition that releases the pharmaceutically acceptable salt ofnaltrexone completely within about 60 minutes.

The invention also provides a method where the administration is chosenfrom the group consisting of oral, sublingual, subcutaneous,intramuscular, intravenous, topical, local, intratracheal, intranasal,transdermal and rectal administration.

The invention also provides for a method where the Immediate releaseformulation is in the form of a rapidly dissolving film, capsule(including soft gel) or tablet.

The invention also provides a method for treating disorders of thecentral nervous system comprising administering to a mammal in needthereof an Immediate release pharmaceutical composition comprisingbetween about 0.01 mg and about 10.0 mg of naltrexone or apharmaceutically acceptable salt thereof.

The invention also provides a method for treating disorders of thecentral nervous system comprising administering to a mammal in needthereof an Immediate release pharmaceutical composition comprisingbetween about 0.01 mg and about 8.0 mg of naltrexone or apharmaceutically acceptable salt thereof.

The invention also provides a method for treating disorders of thecentral nervous system comprising administering to a mammal in needthereof an Immediate release pharmaceutical composition comprisingbetween about 0.01 mg and about 6.0 mg of naltrexone or apharmaceutically acceptable salt thereof.

The invention also provides a method for treating or preventingdisorders of the central nervous system comprising administering to amammal in need thereof an Immediate release pharmaceutical compositioncomprising between about 0.01 mg and about 4.5 mg of naltrexone or apharmaceutically acceptable salt thereof.

The invention also provides a method for treating a disorder of thecentral nervous system chosen from the group consisting ofschizophrenia, schizoaffective disorders, schizophreniform disorders,delusional syndromes and other psychotic conditions related and notrelated to taking psychoactive substances, affective disorder, bipolardisorder, mania, depression, anxiety disorders of various aetiology,stress reactions, conciousness disorders, coma, delirium of alcoholic orother aetiology, aggression, psychomotor agitation and other conductdisorders, sleep disorders of various aetiology, withdrawal syndomes ofvarious aetiology, addiction, pain syndromes of various aetiology,intoxication with psychoactive substances, cerebral circulatorydisorders of various aetiology, psychosomatic disorders of variousartiology, conversion disorders, dissociative disorders, urinationdisorders, autism and other developmental disorders, including nocturia,stuttering, tics, cognitive disorders of various types, includingAlzheimer's disease, Parkinson disease, psychopatological symptoms andneurological disorders in the course of other diseases of the centraland peripheral nervous systems.

The invention also provides for a method where the administration isonce in a 24 hour period.

The invention also provides for a method of treating a human.

The invention also provides for a method where the pharmaceuticallyacceptable salt is the hydrochloride salt of naltrexone.

The invention also provides a method where the Immediate releaseformulation releases the pharmaceutically acceptable salt of naltrexonecompletely within about 60 minutes.

The invention also provides a method where the administration is chosenfrom the group consisting of oral, sublingual, subcutaneous,intramuscular, intravenous, topical, local, intratracheal, intranasal,transdermal and rectal administration.

The invention also provides a method where the Immediate releaseformulation is in the form of a rapidly dissolving film, capsules(including soft gel) or tablet.

The invention also provides a method for treating cardiovasculardisorders comprising administering to a mammal in need thereof anImmediate release pharmaceutical composition comprising between about0.01 mg and about 10.0 mg of naltrexone or a pharmaceutically acceptablesalt thereof.

The invention also provides a method for treating or preventingcardiovascular disorders comprising administering to a mammal in needthereof between about 1.0 mg and about 8.0 mg of naltrexone or apharmaceutically acceptable salt thereof in an Immediate releaseformulation.

The invention also provides a method for treating cardiovasculardisorders comprising administering to a mammal in need thereof betweenabout 0.05 mg and about 6.0 mg of naltrexone or a pharmaceuticallyacceptable salt thereof in an Immediate release formulation.

The invention also provides a method for treating cardiovasculardisorders comprising administering to a mammal in need thereof betweenabout 0.05 mg and about 4.5 mg of naltrexone or a pharmaceuticallyacceptable salt thereof in an Immediate release formulation.

The invention also provides a method where the cardiovascular disorderis chosen from the group consisting of myocardial infarction, stroke,thrombosis, hypertension, heart failure, cardiomyopathy, myocarditis,vascular stenosis, restenosis, atherosclerosis and arterial hyperplasia.

The invention also provides a method where the administration is once ina 24 hour period.

The invention also provides a method of treatment of a human.

The invention also provides a method where the pharmaceuticallyacceptable salt is the hydrochloride salt of naltrexone.

The invention also provides a method using an Immediate releasecomposition that releases the pharmaceutically acceptable salt ofnaltrexone completely within about 60 minutes.

The invention also provides a method where the route of administrationis chosen from the group consisting of oral, sublingual, subcutaneous,intramuscular, intravenous, topical, local, intratracheal, intranasal,transdermal and rectal administration.

The invention also provides a method where the Immediate releasecomposition is in the form of a rapidly dissolving film, capsules(including soft gel) or tablet.

The invention also provides a method for modulating the length oftelomeres in the cells of a mammal comprising administering an Immediaterelease pharmaceutical composition comprising between about 0.01 mg andabout 10.0 mg of naltrexone or a pharmaceutically acceptable saltthereof.

The invention also provides a method where the modulation of telomeresis an increase or stabilization of telomere length.

The invention also provides a method for modulating the length oftelomeres in the cells of a mammal comprising administering an Immediaterelease pharmaceutical composition comprising between about 0.01 mg andabout 8.0 mg of naltrexone or a pharmaceutically acceptable saltthereof.

The invention also provides a method for modulating the length oftelomeres in the cells of a mammal comprising administering an Immediaterelease pharmaceutical composition comprising between about 0.01 mg andabout 6.0 mg of naltrexone or a pharmaceutically acceptable saltthereof.

The invention also provides a method for modulating the length oftelomeres in the cells of a mammal comprising administering an Immediaterelease pharmaceutical composition comprising between about 0.01 mg andabout 4.5 mg of naltrexone or a pharmaceutically acceptable saltthereof.

The invention also provides a method where the administration is once ina 24 hour period.

The invention also provides a method where the mammal is a human.

The invention also provides a method where the pharmaceuticallyacceptable salt is the hydrochloride salt of naltrexone.

The invention also provides a method where the Immediate releasecomposition releases the pharmaceutically acceptable salt of naltrexonecompletely within about 60 minutes.

The invention also provides a method where the administration is chosenfrom the group consisting of oral, sublingual, subcutaneous,intramuscular, intravenous, topical, local, intratracheal, intranasal,transdermal and rectal administration.

The invention also provides a method where the Immediate releasecomposition is in the form of a rapidly dissolving film, capsule(including soft gels) or tablet.

The invention also provides a method for inhibiting angiogenesis in amammal comprising administering an Immediate release pharmaceuticalcomposition comprising between about 0.01 mg and about 10.0 mg ofnaltrexone or a pharmaceutically acceptable salt thereof.

The invention also provides a method for inhibiting angiogenesis in amammal comprising administering an Immediate release pharmaceuticalcomposition comprising between about 0.01 mg and about 8.0 mg ofnaltrexone or a pharmaceutically acceptable salt thereof.

The invention also provides a method for inhibiting angiogenesis in amammal comprising administering an Immediate release pharmaceuticalcomposition comprising between about 0.01 mg and about 6.0 mg ofnaltrexone or a pharmaceutically acceptable salt thereof.

The invention also provides a method for inhibiting angiogenesis in amammal comprising administering an Immediate release pharmaceuticalcomposition comprising between about 0.01 mg and about 4.5 mg ofnaltrexone or a pharmaceutically acceptable salt thereof.

The invention also provides a method where the administration is once ina 24 hour period.

The invention also provides a method of treatment of a human.

The invention also provides a method where the pharmaceuticallyacceptable salt is the hydrochloride salt of naltrexone.

The invention also provides a method where the Immediate releasecomposition releases the pharmaceutically acceptable salt of naltrexonecompletely within about 60 minutes.

The invention also provides a method where the administration is chosenfrom the group consisting of oral, sublingual, subcutaneous,intramuscular, intravenous, topical, local, intratracheal, intranasal,transdermal and rectal administration.

The invention also provides a method where the Immediate releasecomposition is in the form of a rapidly dissolving film, capsule(including soft gel) or tablet.

The invention also provides a method for inducing a sustained immuneresponse in a mammal comprising administering an Immediate releasepharmaceutical composition comprising between about 0.01 mg and about10.0 mg of naltrexone or a pharmaceutically acceptable salt thereof.

The invention also provides a method for inducing a sustained immuneresponse in a mammal comprising administering an Immediate releasepharmaceutical composition comprising between about 0.01 mg and about8.0 mg of naltrexone or a pharmaceutically acceptable salt thereof.

The invention also provides a method for inducing a sustained immuneresponse in a mammal comprising administering an Immediate releasepharmaceutical composition comprising between about 0.01 mg and about6.0 mg of naltrexone or a pharmaceutically acceptable salt thereof.

The invention also provides a method for inducing a sustained immuneresponse in a mammal comprising administering an Immediate releasepharmaceutical composition comprising between about 0.01 mg and about4.5 mg of naltrexone or a pharmaceutically acceptable salt thereof.

The invention also provides a method where the administration is once ina 24 hour period.

The invention also provides a method where the mammal is a human.

The invention also provides a method where the pharmaceuticallyacceptable salt is the hydrochloride salt of naltrexone.

The invention also provides a method where the Immediate releasecomposition releases the pharmaceutically acceptable salt of naltrexonecompletely within about 60 minutes.

The invention also provides a method where the administration is chosenfrom the group consisting of oral, sublingual, subcutaneous,intramuscular, intravenous, topical, local, intratracheal, intranasal,transdermal and rectal administration.

The invention also provides a method where the Immediate releasecomposition is in the form of a rapidly dissolving film, capsule(including soft gels) or tablet.

Terms and Definitions Used

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refers toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. For example, such salts include salts from ammonia,L-arginine, betaine, benethamine, benzathine, calcium hydroxide,choline, deanol, diethanolamine (2,2′-iminobis(ethanol)), diethylamine,2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine,N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,triethanolamine (2,2′,2″-nitrilotris(ethanol)), tromethamine, zinchydroxide, acetic acid, 2,2-dichloro-acetic acid, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoricacid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citricacid, cyclamic acid, decanoic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formicacid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonicacid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid,hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid,isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine,maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid,methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionicacid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid. Further pharmaceutically acceptable salts can beformed with cations from metals such as aluminium, calcium, lithium,magnesium, potassium, sodium, zinc and the like (see Pharmaceuticalsalts, Berge, S. M. et al., J. Pharm. Sci., (1977), Vol. 66, pp. 1-19).Pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound, which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof. Salts of other acids than thosementioned above which for example are useful for purifying or isolatingthe naltrexone (e.g. trifluoro acetate salts), also comprise a part ofthe invention.

Typically, a pharmaceutically acceptable salt of a compound ofnaltrexone may be readily prepared by using a desired acid or base asappropriate. The salt may precipitate from solution and be collected byfiltration or may be recovered by evaporation of the solvent. Forexample, an aqueous solution of an acid such as hydrochloric acid may beadded to an aqueous suspension of a compound of naltrexone and theresulting mixture evaporated to dryness (lyophilized) to obtain the acidaddition salt as a solid. Alternatively, a compound of naltrexone may bedissolved in a suitable solvent, for example an alcohol such asisopropanol, and the acid may be added in the same solvent or anothersuitable solvent. The resulting acid addition salt may then beprecipitated directly, or by addition of a less polar solvent such asdiisopropyl ether or hexane, and isolated by filtration.

The acid addition salts of the compounds of naltrexone may be preparedby contacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the invention.

Also included are both total and partial salts, that is to say saltswith 1, 2 or 3, preferably 2, equivalents of base per mole of acid offormula I or salts with 1, 2 or 3 equivalents, preferably 1 equivalent,of acid per mole of base of formula I.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates of the compound of the invention arewithin the scope of the invention. The salts of naltrexone may formsolvates (e.g., hydrates) and the invention also includes all suchsolvates. The meaning of the word “solvates” is well known to thoseskilled in the art as a compound formed by interaction of a solvent anda solute (i.e., solvation). Techniques for the preparation of solvatesare well established in the art (see, for example, Brittain.Polymorphism in Pharmaceutical Solids. Marcel Decker, New York, 1999.).

The invention also encompasses prodrugs of the compounds of formula I,i.e., compounds which release an active parent drug (naltrexone) in vivowhen administered to a mammalian subject. A prodrug is apharmacologically active or more typically an inactive compound that isconverted into a pharmacologically active agent by a metabolictransformation. Prodrugs of naltrexone are prepared by modifyingfunctional groups present in naltrexone in such a way that themodifications may be cleaved in vivo to release the parent compound. Invivo, a prodrug readily undergoes chemical changes under physiologicalconditions (e.g., are acted on by naturally occurring enzyme(s))resulting in liberation of the pharmacologically active agent. Prodrugsof naltrexone wherein a hydroxyl or amino, of naltrexone is bonded toany group that may be cleaved in vivo to regenerate the free hydroxyl,amino or carboxy group, respectively. Examples of prodrugs includeesters (e.g., acetate, formate, and benzoate derivatives) of compoundsof formula I or any other derivative, which upon being brought to thephysiological pH or through enzyme action is converted to the activeparent drug. Conventional procedures for the selection and preparationof suitable prodrug derivatives are described in the art (see, forexample, Bundgaard. Design of Prodrugs. Elsevier, 1985). Prodrugs may beadministered in the same manner as the active ingredient to which theyconvert or they may be delivered in a reservoir form, e.g., atransdermal patch or other reservoir which is adapted to permit (byprovision of an enzyme or other appropriate reagent) conversion of aprodrug to the active ingredient slowly over time, and delivery of theactive ingredient to the patient.

The term “carrier” refers to a diluent, excipient, and/or vehicle withwhich an active compound is administered. The pharmaceuticalcompositions of the invention may contain combinations of more than onecarrier. Such pharmaceutical carriers can be sterile liquids, such aswater, saline solutions, aqueous dextrose solutions, aqueous glycerolsolutions, and oils, including those of petroleum, animal, vegetable orsynthetic origin, such as peanut oil, soybean oil, mineral oil, sesameoil and the like. Water or aqueous solution saline solutions and aqueousdextrose and glycerol solutions are preferably employed as carriers,particularly for injectable solutions. Suitable pharmaceutical carriersare described in “Remington's Pharmaceutical Sciences” by E. W. Martin,18th Edition.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes an excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the present application includes both one and more than one suchexcipient.

Naltrexone may be formulated for administration in any convenient wayfor use in human or veterinary medicine and the invention thereforeincludes within its scope pharmaceutical compositions comprising acompound of the invention adapted for use in human or veterinarymedicine. Such compositions may be presented for use in a conventionalmanner with the aid of one or more suitable carriers. Acceptablecarriers for therapeutic use are well-known in the pharmaceutical art,and are described, for example, in Remington's Pharmaceutical Sciences,Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice ofpharmaceutical carrier can be selected with regard to the intended routeof administration and standard pharmaceutical practice. Thepharmaceutical compositions may comprise as, in addition to, the carrierany suitable binder(s), lubricant(s), suspending agent(s), coatingagent(s), and/or solubilizing agent(s).

Pharmaceutical Compositions Comprising Naltrexone

While it is possible that a naltrexone may be administered as the bulksubstance, it is preferable to present the active ingredient in apharmaceutical formulation, e.g., wherein the agent is in admixture witha pharmaceutically acceptable carrier selected with regard to theintended route of administration and standard pharmaceutical practice.

Accordingly, the invention further provides a pharmaceutical compositioncomprising naltrexone or pharmaceutically acceptable salt thereof inadmixture with a pharmaceutically acceptable carrier. The term “carrier”refers to a diluent, excipient, and/or vehicle with which an activecompound is administered.

Naltrexone may be used in combination with other therapies and/or activeagents.

Accordingly, the invention provides, in a further aspect, apharmaceutical composition comprising naltrexone or a solvate, hydrate,enantiomer, diastereomer, N-oxide or pharmaceutically acceptable saltthereof, a second active agent, and a pharmaceutically acceptablecarrier.

The pharmaceutical compositions may comprise as, in addition to, thecarrier any suitable binder, lubricant, suspending agent, coating agentand/or solubilizing agent. Preservatives, stabilizers, dyes andflavoring agents also may be provided in the pharmaceutical composition.Antioxidants and suspending agents may be also used.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention may beprepared by processes known in the art, for example see WO02/00196.

The term “Immediate release” is defined as a release of compound from adosage form in a relatively brief period of time, generally up to about60 minutes.

Routes of Administration and Unit Dosage Forms

The routes for administration include oral (e.g., as a tablet, capsule,or as an ingestible solution), topical, mucosal (e.g., as a nasal sprayor aerosol for inhalation), nasal, parenteral (e.g., by an injectableform), gastrointestinal, intraspinal, intraperitoneal, intramuscular,intravenous, intrauterine, intraocular, intradermal, intracranial,intratracheal, intravaginal, intracerebroventricular, intracerebral,subcutaneous, ophthalmic (including intravitreal or intracameral),transdermal, rectal, buccal, epidural and sublingual. The compositionsof the invention may be especially formulated for any of thoseadministration routes. In preferred embodiments, the pharmaceuticalcompositions of the invention are formulated in a form that is suitablefor oral delivery.

There may be different composition/formulation requirements depending onthe different delivery systems. It is to be understood that not all ofthe compounds need to be administered by the same route. Likewise, ifthe composition comprises more than one active component, then thosecomponents may be administered by different routes. By way of example,the pharmaceutical composition of the invention may be formulated to bedelivered using a mini-pump or by a mucosal route, for example, as anasal spray or aerosol for inhalation or ingestible solution, orparenterally in which the composition is formulated by an injectableform, for delivery, by, for example, an intravenous, intramuscular orsubcutaneous route. Alternatively, the formulation may be designed to bedelivered by multiple routes.

Where the agent is to be delivered mucosally through thegastrointestinal mucosa, it should be able to remain stable duringtransit though the gastrointestinal tract; for example, it should beresistant to proteolytic degradation, stable at acid pH and resistant tothe detergent effects of bile. For example, naltrexone may be coatedwith an enteric coating layer. The enteric coating layer material may bedispersed or dissolved in either water or in a suitable organic solvent.As enteric coating layer polymers, one or more, separately or incombination, of the following can be used; e.g., solutions ordispersions of methacrylic acid copolymers, cellulose acetate phthalate,cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, polyvinyl acetatephthalate, cellulose acetate trimellitate, carboxymethylethylcellulose,shellac or other suitable enteric coating layer polymer(s). Forenvironmental reasons, an aqueous coating process may be preferred. Insuch aqueous processes methacrylic acid copolymers are most preferred.

When appropriate, the pharmaceutical compositions can be administered byinhalation, in the form of a suppository or pessary, topically in theform of a lotion, solution, cream, ointment or dusting powder, by use ofa skin patch, orally in the form of tablets containing excipients suchas starch or lactose, or in capsules or ovules either alone or inadmixture with excipients, or in the form of elixirs, solutions orsuspensions containing flavouring or colouring agents, or they can beinjected parenterally, for example intravenously, intramuscularly orsubcutaneously. For buccal or sublingual administration the compositionsmay be administered in the form of tablets or lozenges, which can beformulated in a conventional manner.

When the composition of the invention is to be administeredparenterally, such administration includes one or more of:intravenously, intraarterially, intraperitoneally, intrathecally,intraventricularly, intraurethrally, intrasternally, intracranially,intramuscularly or subcutaneously administering the agent; and/or byusing infusion techniques.

Pharmaceutical compositions of the invention can be administeredparenterally, e.g., by infusion or injection. Pharmaceuticalcompositions suitable for injection or infusion may be in the form of asterile aqueous solution, a dispersion or a sterile powder that containsthe active ingredient, adjusted, if necessary, for preparation of such asterile solution or dispersion suitable for infusion or injection. Thispreparation may optionally be encapsulated into liposomes. In all cases,the final preparation must be sterile, liquid, and stable underproduction and storage conditions. To improve storage stability, suchpreparations may also contain a preservative to prevent the growth ofmicroorganisms. Prevention of the action of micro-organisms can beachieved by the addition of various antibacterial and antifungal agents,e.g., paraben, chlorobutanol, or ascorbic acid. In many cases isotonicsubstances are recommended, e.g., sugars, buffers and sodium chloride toassure osmotic pressure similar to those of body fluids, particularlyblood. Prolonged absorption of such injectable mixtures can be achievedby introduction of absorption-delaying agents, such as aluminiummonostearate or gelatin.

Dispersions can be prepared in a liquid carrier or intermediate, such asglycerin, liquid polyethylene glycols, triacetin oils, and mixturesthereof. The liquid carrier or intermediate can be a solvent or liquiddispersive medium that contains, for example, water, ethanol, a polyol(e.g., glycerol, propylene glycol or the like), vegetable oils,non-toxic glycerine esters and suitable mixtures thereof. Suitableflowability may be maintained, by generation of liposomes,administration of a suitable particle size in the case of dispersions,or by the addition of surfactants.

For parenteral administration, the compound is best used in the form ofa sterile aqueous solution, which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. The aqueous solutions should be suitably buffered (preferably toa pH of from 3 to 9), if necessary. The preparation of suitableparenteral formulations under sterile conditions is readily accomplishedby standard pharmaceutical techniques well-known to those skilled in theart.

Sterile injectable solutions can be prepared by mixing a compound offormula I with an appropriate solvent and one or more of theaforementioned carriers, followed by sterile filtering. In the case ofsterile powders suitable for use in the preparation of sterileinjectable solutions, preferable preparation methods include drying invacuum and lyophilization, which provide powdery mixtures of thealdosterone receptor antagonists and desired excipients for subsequentpreparation of sterile solutions.

The compound according to the invention may be formulated for use inhuman or veterinary medicine by injection (e.g., by intravenous bolusinjection or infusion or via intramuscular, subcutaneous or intrathecalroutes) and may be presented in unit dose form, in ampoules, or otherunit-dose containers, or in multi-dose containers, if necessary with anadded preservative. The compositions for injection may be in the form ofsuspensions, solutions, or emulsions, in oily or aqueous vehicles, andmay contain formulatory agents such as suspending, stabilizing,solubilizing and/or dispersing agents. Alternatively, the activeingredient may be in sterile powder form for reconstitution with asuitable vehicle, e.g., sterile, pyrogen-free water, before use.

Naltrexone can be administered (e.g., orally or topically) in the formof tablets, rapidly dissolving films, capsules, ovules, elixirs,solutions or suspensions, which may contain flavoring or coloringagents, for Immediate-, delayed-, modified-, sustained-, pulsed-orcontrolled-release applications.

Naltrexone may also be presented for human or veterinary use in a formsuitable for oral or buccal administration, for example in the form ofsolutions, gels, syrups, mouth washes or suspensions, or a dry powderfor constitution with water or other suitable vehicle before use,optionally with flavoring and coloring agents. Solid compositions suchas tablets, rapidly dissolving films, capsules, lozenges, pastilles,pills, boluses, powder, pastes, granules, bullets or premix preparationsmay also be used. Solid and liquid compositions for oral use may beprepared according to methods well-known in the art. Such compositionsmay also contain one or more pharmaceutically acceptable carriers andexcipients which may be in solid or liquid form.

The tablets may contain excipients such as microcrystalline cellulose,lactose, sodium citrate, calcium carbonate, dibasic calcium phosphateand glycine, disintegrants such as starch (preferably corn, potato ortapioca starch), sodium starch glycolate, croscarmellose sodium andcertain complex silicates, and granulation binders such aspolyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.

Additionally, lubricating agents such as magnesium stearate, stearicacid, glyceryl behenate and talc may be included.

The compositions may be administered orally, in the form of rapid orcontrolled release tablets, microparticles, mini tablets, capsules,sachets, and oral solutions or suspensions, or powders for thepreparation thereof. In addition to the new solid-state forms ofpantoprazole of the invention as the active substance, oral preparationsmay optionally include various standard pharmaceutical carriers andexcipients, such as binders, fillers, buffers, lubricants, glidants,dyes, disintegrants, odourants, sweeteners, surfactants, mold releaseagents, antiadhesive agents and coatings. Some excipients may havemultiple roles in the compositions, e.g., act as both binders anddisintegrants.

Examples of pharmaceutically acceptable disintegrants for oralcompositions include starch, pre-gelatinized starch, sodium starchglycolate, sodium carboxymethylcellulose, croscarmellose sodium,microcrystalline cellulose, alginates, resins, surfactants, effervescentcompositions, aqueous aluminum silicates and cross-linkedpolyvinylpyrrolidone.

Examples of pharmaceutically acceptable binders for oral compositionsinclude acacia; cellulose derivatives, such as methylcellulose,carboxymethylcellulose, hydroxypropylmethylcellulose,hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose,dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol,starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates,magnesium-aluminum silicate, polyethylene glycol or bentonite.

Examples of pharmaceutically acceptable fillers for oral compositionsinclude lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose,mannitol, sorbitol, starch, cellulose (particularly microcrystallinecellulose), dihydro- or anhydro-calcium phosphate, calcium carbonate andcalcium sulphate.

Examples of pharmaceutically acceptable lubricants useful in thecompositions of the invention include magnesium stearate, talc,polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulphate,magnesium lauryl sulphate, sodium oleate, sodium stearyl fumarate, andcolloidal silicon dioxide.

Examples of suitable pharmaceutically acceptable odourants for the oralcompositions include synthetic aromas and natural aromatic oils such asextracts of oils, flowers, fruits (e.g., banana, apple, sour cherry,peach) and combinations thereof, and similar aromas. Their use dependson many factors, the most important being the organoleptic acceptabilityfor the population that will be taking the pharmaceutical compositions.

Examples of suitable pharmaceutically acceptable dyes for the oralcompositions include synthetic and natural dyes such as titaniumdioxide, beta-carotene and extracts of grapefruit peel.

Examples of useful pharmaceutically acceptable coatings for the oralcompositions, typically used to facilitate swallowing, modify therelease properties, improve the appearance, and/or mask the taste of thecompositions include hydroxypropylmethylcellulose,hydroxypropylcellulose and acrylate-methacrylate copolymers.

Examples of pharmaceutically acceptable sweeteners for the oralcompositions include aspartame, saccharin, saccharin sodium, sodiumcyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.

Examples of pharmaceutically acceptable buffers include citric acid,sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesiumoxide, calcium carbonate and magnesium hydroxide.

Examples of pharmaceutically acceptable surfactants include sodiumlauryl sulphate and polysorbates.

Solid compositions of a similar type may also be employed as fillers ingelatin capsules. Preferred excipients in this regard include lactose,starch, a cellulose, milk sugar or high molecular weight polyethyleneglycols. For aqueous suspensions and/or elixirs, the agent may becombined with various sweetening or flavoring agents, coloring matter ordyes, with emulsifying and/or suspending agents and with diluents suchas water, ethanol, propylene glycol and glycerin, and combinationsthereof.

Naltrexone may also, for example, be formulated as suppositories e.g.,containing conventional suppository bases for use in human or veterinarymedicine or as pessaries e.g., containing conventional pessary bases.

Naltrexone may be formulated for topical administration, for use inhuman and veterinary medicine, in the form of ointments, creams, gels,hydrogels, lotions, solutions, shampoos, powders (including spray ordusting powders), pessaries, tampons, sprays, dips, aerosols, drops(e.g., eye ear or nose drops) or pour-ons.

For application topically to the skin, the agent of the invention can beformulated as a suitable ointment containing the active compoundsuspended or dissolved in, for example, a mixture with one or more ofthe following: mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax, sorbitan monostearate, a polyethylene glycol, liquid paraffin,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol, and water. Such compositions may also contain otherpharmaceutically acceptable excipients, such as polymers, oils, liquidcarriers, surfactants, buffers, preservatives, stabilizers,antioxidants, moisturizers, emollients, colourants, and odourants.

Examples of pharmaceutically acceptable polymers suitable for suchtopical compositions include acrylic polymers; cellulose derivatives,such as carboxymethylcellulose sodium, methylcellulose orhydroxypropylcellulose; natural polymers, such as alginates, tragacanth,pectin, xanthan and cytosan.

Examples of suitable pharmaceutically acceptable oils which are souseful include mineral oils, silicone oils, fatty acids, alcohols, andglycols.

Examples of suitable pharmaceutically acceptable liquid carriers includewater, alcohols or glycols such as ethanol, isopropanol, propyleneglycol, hexylene glycol, glycerol and polyethylene glycol, or mixturesthereof in which the pseudopolymorph is dissolved or dispersed,optionally with the addition of non-toxic anionic, cationic or non-ionicsurfactants, and inorganic or organic buffers.

Examples of pharmaceutically acceptable preservatives include sodiumbenzoate, ascorbic acid, esters of p-hydroxybenzoic acid and variousantibacterial and antifungal agents such as solvents, for exampleethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternaryammonium salts, and parabens (such as methyl paraben, ethyl paraben andpropyl paraben).

Examples of pharmaceutically acceptable stabilizers and antioxidantsinclude ethylenediaminetetraacetic acid (EDTA), thiourea, tocopherol andbutyl hydroxyanisole.

Examples of pharmaceutically acceptable moisturizers include glycerine,sorbitol, urea and polyethylene glycol.

Examples of pharmaceutically acceptable emollients include mineral oils,isopropyl myristate, and isopropyl palmitate.

The compounds may also be dermally or transdermally administered, forexample, by use of a skin patch.

For ophthalmic use, the compounds can be formulated as micronizedsuspensions in isotonic, pH adjusted, sterile saline, or, preferably, assolutions in isotonic, pH adjusted, sterile saline, optionally incombination with a preservative such as a benzylalkonium chloride.

As indicated, naltrexone can be administered intranasally or byinhalation and is conveniently delivered in the form of a dry powderinhaler or an aerosol spray presentation from a pressurized container,pump, spray or nebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, a hydrofluoroalkane such as1,1,1,2-tetrafluoroethane (HFA 134AT) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Thepressurized container, pump, spray or nebulizer may contain a solutionor suspension of the active compound, e.g., using a mixture of ethanoland the propellant as the solvent, which may additionally contain alubricant, e.g., sorbitan trioleate.

Capsules and cartridges (made, for example, from gelatin) for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound and a suitable powder base such as lactose or starch.

For topical administration by inhalation the compounds according to theinvention may be delivered for use in human or veterinary medicine via anebulizer.

The pharmaceutical compositions of the invention may contain from 0.01to 99% weight per volume of the active material. For topicaladministration, for example, the composition will generally contain from0.01-10%, more preferably 0.01-1% of the active material.

Naltrexone can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The pharmaceutical composition or unit dosage form of the invention maybe administered according to a dosage and administration regimen definedby routine testing in the light of the guidelines given above in orderto obtain optimal activity while minimizing toxicity or side effects fora particular patient. However, such fine tuning of the therapeuticregimen is routine in the light of the guidelines given herein.

The dosage of the active agents of the invention may vary according to avariety of factors such as underlying disease conditions, theindividual's condition, weight, gender and age, and the mode ofadministration. An effective amount for treating a disorder can easilybe determined by empirical methods known to those of ordinary skill inthe art, for example by establishing a matrix of dosages and frequenciesof administration and comparing a group of experimental units orsubjects at each point in the matrix. The exact amount to beadministered to a patient will vary depending on the state and severityof the disorder and the physical condition of the patient. A measurableamelioration of any symptom or parameter can be determined by a personskilled in the art or reported by the patient to the physician.

The pharmaceutical composition or unit dosage form may be administeredin a single daily dose, or the total daily dosage may be administered individed doses. In addition, co-administration or sequentialadministration of another compound for the treatment of the disorder maybe desirable. To this purpose, the combined active principles areformulated into a simple dosage unit.

For combination treatment where the compounds are in separate dosageformulations, the compounds can be administered concurrently, or eachcan be administered at staggered intervals. For example, the compound ofthe invention may be administered in the morning and the additionalantiviral compound may be administered in the evening, or vice versa.Additional compounds may be administered at specific intervals too. Theorder of administration will depend upon a variety of factors includingage, weight, gender and medical condition of the patient; the severityand aetiology of the disorders to be treated, the route ofadministration, the renal and hepatic function of the patient, thetreatment history of the patient, and the responsiveness of the patient.Determination of the order of administration may be fine-tuned and suchfine-tuning is routine in the light of the guidelines given herein.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, an Immediate releasenaltrexone composition comprising between about 0.01 mg and about 10 mgof naltrexone may be administered to patients suffering from humanimmunodeficiency virus (HIV) acquired immune deficiency syndrome (AIDS,autoimmune disease, cancer, cardio vascular disease, inflammatorydiseases, chronic inflammation, inflammatory bowel disease,Musculo-skeletal disorders, metabolic disorders and neurodegenerativediseases in the form of an Immediate release naltrexone tablets, rapidlydissolving films, liquids and cream, comprising from about 0.01 mg toabout 10 mg of naltrexone in adults and about 0.05 to about 4.5 mg ofnaltrexone in children with suitable pharmaceutically-acceptableexcipients, binders, sweeteners, coloring agents and other conventionaladditives.

Where high dose naltrexone and slow release naltrexone comprisingbetween about 0.01 mg and about 10 mg of naltrexone and Immediaterelease naltrexone comprising between about 0.01 mg and about 10 mg ofnaltrexone share commonality” in categories of genes and are consideredthe same drug the difference in dosing and delivery method (Immediaterelease) difference in the overall response to the immune system.

There is a difference in the cell patterns of genes that are altered bythe treatment of Immediate release naltrexone verses high doesnaltrexone and slow release low naltrexone comprises between about 0.01mg and about 10 mg of naltrexone. The differences are important becauseImmediate release naltrexone comprising between about 0.01 and about 10mg of naltrexone has as immunomodulator. Since Immediate releasenaltrexone blocks the opiate receptors only for a few hours before it isnaturally excreted, what results is a rebound effect; in which both theproduction and utilization of met (5) enkelphine or opiate growth factorare increased. Once the Immediate release naltrexone has beenmetabolized, the elevated endorphins produced as a result of the reboundeffect can now interact with the more-sensitive and more-plentifulreceptors and assist in regulating cell growth and immunity. There isnot rebound effect with either high dose naltrexone or slow releasenaltrexone and it is the rebound immunomodulatory effect that effectsthe treatment of treating patients suffering from human immunodeficiencyvirus (HIV) acquired immune deficiency syndrome (AIDS, autoimmunedisease, opportunistic infections, cancer, inflammation, andneurodegenerative diseases The preferred method, an Immediate releasenaltrexone composition administered to patients in one daily dose whichcomprises about 0.01 to about 10 mg of naltrexone. The preferred timefor dosing is after 8 PM to 11 PM bedtime but can be used in the morningas well.

The method of the present invention not only provides dramaticsymptomatic relief for patients suffering from human immunodeficiencyvirus (HIV) acquired immune deficiency syndrome (AIDS, autoimmunedisease, cancer, cardio vascular disease, inflammatory diseases, chronicinflammation, inflammatory bowel disease, Musculo-skeletal disorders,metabolic disorders and neurodegenerative diseases for exampleAlzheimer's, Asthma, Atopic Dermatitis Addison's disease Alopecia orAlopecia Areata, Antiphospholipid Syndrome, Autism, AutoimmuneHepatitis, Autoimmune hemolytic anemia, Autoimmune pancreatitis (AIP),Bullus pemphigoid, Celiac disease, Chronic bullous disease of childhood,Chronic sinusitis, Chronic inflammatory demyelinatingPolyradiculoneuropathy (CIDP), Cictricial pemphigoid (CP), Depression,Complex Regional Pain Syndrome (CRPS), Crohn's Disease, Dermatitisherpetiformis (DH), Dermatomyositis, Evans syndrome, Ehlers DanlosSyndrome (EDS), Fatty liver, Graves' Disease Gullain-Barre syndrome,Hashimoto's, Inflammatory bowel diseases (colitis, enteritis andileitis), HIV/AIDS, Insulin-dependent diabetes, Meniere's Disease, Mixedconnective tissue disease or MCTD, Myasthenia, Multiple SclerosisMultifocal motor neuropath, Neuromyotonia or Isaac's Palindromic ReflexSympathetic Dystropy (RSD), Rheumatism, Pemphigus vulgaris causes,Pemphigus follaceus PF), Pemphigoid gestationis, Pernicious AnemiaParaneoplastic Pemphigus (PNP), Polymyalgia Rheumatica, Psoriasis,Psoriatic arthritis, Raynaud's phenomenon, Reactive Arthritis,Retinopathy, Rheumatoid arthritis, Sjogren's syndrome, Systemic lupuserythematosus, Systemic sclerosis (scleroderma) Thromboangiitisobliterans, Thyroiditis with hypothyroidism, Type I autoimmunepolyglandular syndrome (PAS), Type II autoimmune polyglandular syndrome,Varicella-zoster virus, Wegener's granulomatosis

Cancer: Adjunct to chemotherapy, breast, Hepatoblastoma, lymphoma,lymphadenopathy, ovarian, b-cell lymphoma, prostate, pancreatic cancerbut has been found to reduce patient's systemic autoantibody level,increase production of increasing proliferation and functionalactivities of CD4+T-cells and CD8+T-cells which will play a role inanti-virus and anti-tumor activities; increasing maturation of dendriticcells which will initiate and intensify T-cell responses; increasingsecretion of cytokines such as IL-2, TNF, IL-12 and IFN-γ which willamplify the T-cell response and mediate interaction among immune cells,including TRL-4 and TRL-9 forming a modulated and balanced immunity;increasing functions of macrophages, resulting in enhanced cellularimmunity through secreting a set of cytokines; and increasing activityof NK cells which have the ability to kill cancer cells andvirus-infected cells, lengthen telomerase slowing cell death potentiallyleading to a true remission in the course of the disease.

The following examples provide a detailed illustration of the method ofthe present invention. These examples are not intended to limit orrestrict the scope of the invention in any way.

EXAMPLES Human Immunodeficiency Virus (HIV) Clinical Trials

A single blind 90 day randomized bridging clinical trial was conductedin Nigeria to evaluate the impact of an Immediate release naltrexonecomposition comprising about 4.5 mg of naltrexone single oral dose onasymptomatic HIV+ adults undergoing antiretroviral (ART) treatment withCD4 counts below 360 average. The differences in CD4 count, CD4%,hemoglobin, viral load, interferon alpha, and standard chemistry panelwere measured between treated versus non-treated groups four timesthroughout the study. The results showed an improvement in CD4 count inthe treatment group was 53 that were significantly greater than thecontrol group (54 subjects) at 3 months with an increase of 44%.Improvement in CD4% in the treatment group was observed throughouttreatment, and the increases were statistically significant. In additionto the changes in CD4 count patients saw an increase in BMI, reductionin opportunistic infections. These data presented herein on patients whohave been placed on an Immediate release naltrexone compositioncomprising between about 0.01 and about 10 mg of naltrexone who haveHIV/AIDS show that it has the ability to be an effectiveimmune-enhancing agent specifically in this disease by increasing orstabilizing a patient's CD4 count or by providing a decline in IFN-αlevels and viral loads. When used alone, it appears to slow and/or stopthe progression of the disease. When used in combination withantivirals, an Immediate release naltrexone composition comprisingbetween about 0.01 mg and about 10 mg appears to accelerate immunesystem healing and increase CD4 levels.

A single blind nine-month randomized clinical trial was conducted inMali to evaluate the impact of an Immediate release naltrexonecomposition comprising about 3 mg of naltrexone on asymptomatic HIV+adults undergoing antiretroviral (ART) treatment with CD4 counts below350 cell/mm3. The differences in CD4 count, CD4%, hemoglobin, viralload, interferon alpha, and standard chemistry panel were measuredbetween treated versus non-treated groups five times throughout thestudy. The results showed an improvement in CD4 count in the treatmentgroup (51 subjects) that was significantly greater than the controlgroup (49 subjects) at 6 months (p=0.041) and marginally at 9 months(p=0.067). Improvement in CD4% in the treatment group was observedthroughout treatment, but these increases were not statisticallysignificant (Traore A K. et al., September 2011). The results wereeffected by the fact the product was compounded and was dosed at 3 mgrather then 4.5 mg

Naltrexone as an adjunct therapy with HIV/AIDS patients. HIV 50 patientsin Africa in conjunction with standard of care, where ART extends liveit does not fully restore health. HIV disease is associated with a newconstellation of problems, generally referred to as “non-AIDSmorbidity”, and, in the popular press, “premature aging. IV replicationare at risk for developing a number of non-AIDS conditions, includingcardiovascular disease, cancer, kidney disease, liver disease,osteopenia/osteoporosis and neurocognitive disease (collectivelyreferred to as “serious non-AIDS events”). Malignancies associated withinfections such as human papilloma virus (including uro-genital and headand neck cancers), Epstein Barr Virus (including Hodgkins disease), andhepatitis B and C (hepatocellular carcinoma), are also relatively commonin HIV-infected adult. A rapidly growing and remarkably consistentevidence base indicates that many markers of inflammation are higher inantiretroviral-treated adults than in age-matched uninfectedindividuals^((30, 31)). Subtle elevations in many of these biomarkersare associated with dramatic increases in the risk of subsequentdisease, including all-cause mortality For example, as compared to awell-matched uninfected population, treated HIV-infected adults haveapproximately 50 to 100% higher levels of the inflammatory cytokineinterleukin-6 (IL-6)⁽³²⁾. Patients taking Naltrexone showed: Secreasedinflammatory cytokine and a shift from Th1 (pro-inflammatory) to Th2(anti-inflammatory) and effect on Treated with immunotherapies/cytokineantibodies (TNF, IL-2, IL-10) as well Affectsmicroglia—macrophages/1^(st) line of immune defense in CNS; normallyquiescent Cell death, inflammation, infection→Activatedmicroglia→increase in proinflammatory cytokines, excitatory amino acids,and nitric oxide (NO) Increased NFκB→additional proinflammatorycytokines that act on neurons to create pain, fatigue, etc. Risk factorsfor impaired CD4 T-cell recovery include low pre-treatment CD4+T cellcount nadir, co-infection with other viruses such as hepatitis C, olderage, and perhaps viral factors (24). Suboptimal treatment-mediated CD4+Tcell outcomes likely have clinical consequences given the consistentassociation between CD4+T cell counts during ART and elevated risk ofmany co-morbidities (e.g., heart disease, cancer) and all-causemortality. Chronic signaling through the interferon-alpha pathway maycontribute to this inflammatory disease⁽³²⁾, as can the impact of virusproduction/entry (without productive infection) on pyroptosis, which isa highly inflammatory process that can cause death of affected andneighboring cells. The frequency of activated T cells remains elevatedduring chronic treatment and appears related to size of the HIVreservoir and pace of immune reconstitution although the effect of thismarker in predicting overall morbidity and mortality is not as strong assome of the innate immune system inflammatory markers⁽³⁷⁾.

Patients saw a reduction in opportunistic infection and a higher qualityof live over the long term. We believe that long term monitoring ofpatients will show a reduction in non-AIDS morbidity.

A single blind nine-month randomized clinical trial was conducted inMali to evaluate the impact of an Immediate release naltrexonecomposition comprising between about 0.01 mg and about 10 mg ofnaltrexone on asymptomatic HIV+ adults undergoing antiretroviral (ART)treatment with CD4 counts below 350 cell/mm3. The differences in CD4count, CD4%, hemoglobin, viral load, interferon alpha, and standardchemistry panel were measured between treated versus non-treated groupsfive times throughout the study. The results showed an improvement inCD4 count in the treatment group (51 subjects) that was significantlygreater than the control group (49 subjects) at 6 months (p=0.041) andmarginally at 9 months (p=0.067). Improvement in CD4% in the treatmentgroup was observed throughout treatment, but these increases were notstatistically significant (Traore A K. et al., September 2011). Theresults on this trial were not an effective because the Immediaterelease naltrexone used was compounded and was only 3 mg rather then 4.5mg which has been shown to be the most effective dose.

A 12-week, placebo-controlled trial of IMMEDIATE RELEASE NALTREXONE(LDN) from 1985-1986 in 38 patients with AIDS. Patients wereadministered 3.0 mg IMMEDIATE RELEASE NALTREXONE (LDN) daily at bedtime.Patients who participated in this trial showed a significant differencein the incidence of opportunistic infections with 5 out of 16 patients(31%) on placebo developing opportunistic infections in comparison to 0of the 22 patients in the Immediate release naltrexone (LDN) group.Other difference between placebo and Immediate release naltrexone (LDN)treated patients included: lymphocyte mitogen responses declined onplacebo and not on Immediate release naltrexone; pathologically elevatedlevels of acid-labile alpha interferon declined significantly in thepatients on Immediate release naltrexone and not in those patients onplacebo (Bihari et al., September 1996).

A study of 55 patients two are trial one with Two Groups One on Epivirand AZT and one group on Epiviver and AZT neither group had taken AZTbefore the study. The Glaxo patients on Epivir and AZT experienced anaverage rise of 40 CD4's at 6 months. This represents an 11.3% increase.The patients on Epivir, AZT and Immediate release 4.5 mg naltrexoneexperienced an average rise of 106 CD4's at 6 months, representing a128% increase. All 19 of the patients in the naltrexone group hadincreases of at least 30%. In addition, there was, in all but one, asignificant increase in energy, appetite and mood. In severalunderweight patients there were weight gains of 10 to 50 pounds in thefirst 2 months with no opportunistic infection. New England Journal ofMedicine of Dec. 21, 1995 (vol. 333, number 25, pg. 1662) reported by aninvestigator working for Glaxo.

Cancer

89 patients Hematologic Cancer Patients This was a randomized controlledtrial assessing quality of life in patients with hematologicmalignancies from a single institute in Hamedan. Patients were allocatedinto two study arms and in addition to their routine treatment receivedeither daily naltrexone 3 mg capsules (treatment group) or 3 mg starch(placebo group) and were followed up for 5 months. Quality of life wasmeasured using the EORTC QLQ-C30 in four points in time (at admission,1, 3 and 5 months follow-up).

Data were analyzed to compare quality of life in two groups. In total,89 patients were studied (45 in treatment group and 44 in placebogroup). There were no significant differences between two groups eitherin demographic and clinical characteristics or in baseline quality oflife scores.

However, at 1 month, 3 and 5-month follow-up assessments significantdifferences were observed. In one month follow-up two groups weresignificantly different in social functioning (p<0.05) indicating abetter condition in the treatment group. In the 3-month follow-up,social functioning, role functioning, nausea and vomiting and appetiteloss were better in the treatment group (all p-values<0.05). In the5-month follow-up, physical functioning, social functioning, rolefunctioning, global quality of life, nausea and vomiting and appetiteloss were significantly better in the naltrexone group. Lodonal or Lowdose naltrexone is an effective drug in improving quality of life inpatients with hematologic cancers undergoing treatment.

Twenty-nine of the patients had Kaposi's sarcoma (K.S.), six previouslyhad a major opportunistic infection (O.I.) and three had both O.I. andK.S. The mean time of the 38 patients from AIDS diagnosis to admissioninto the study was 7.6 months. Thirty-one of the 38 patients had abaseline absolute T4 count of less than 300/ml. Immediate releasenaltrexone was administered at a dose of 1.75 mg nightly at bedtime.During the 3-month double-blind period, a significant drop in elevatedlevels of serum alpha interferon (IFN-α) was observed in those patientsreceiving LDN compared with the placebo patients (p<0.01). Aftercompletion of this double blind period, all of the 38 patients wereplaced on Immediate release naltrexone. Twenty-three of the 38 patientsshowed a marked decline in IFN-α levels (from means of 144.9 IU. to 11.0IU. over a 12-month period) while the remaining 15 did not show such adecline. Nineteen of the 23 (83%) who showed a decline in IFN-α survivedwhile only 2 of the 15 (13%) who did not show such a decline survived(p<0.01). No side effects were noted during the conduct of this trial.

This study aimed to investigate its effect on hematologic cancerpatients. This was a randomized controlled trial assessing quality oflife in patients with hematologic malignancies from a single institute.Patients were allocated into two study arms and in addition to theirroutine treatment received either daily Immediate release naltrexone 3mg capsules (treatment group) or 3 mg starch (placebo group) and werefollowed up for 5 months. Quality of life was measured using the EORTCQLQ-C30 in four points in time (at admission, 1, 3 and 5 monthsfollow-up). Data were analyzed to compare quality of life in two groups.Totally, 89 patients were studied (45 in treatment group and 44 inplacebo group). There were no significant differences between two groupseither in demographic and clinical characteristics or in baselinequality of life scores. However, at 1 month, 3 and 5-month follow-upassessments significant differences were observed. In one monthfollow-up two groups were significantly different in social functioning(p<0.05) indicating a better condition in the treatment group. In the3-month follow-up, social functioning, role functioning, nausea andvomiting and appetite loss were better in the treatment group (allp-values<0.05). In the 5-month follow-up, physical functioning, socialfunctioning, role functioning, global quality of life, nausea andvomiting and appetite loss were significantly better in the Immediaterelease naltrexone group. Immediate release naltrexone between 0.01 to10 mg is an effective drug in improving quality of life in patients withhematologic cancers. Most importantly, there were no changes in theblood laboratory tests with Immediate release naltrexone. Compared tostandard chemotherapy that reduces the blood count from bone marrowtoxicity, white blood cell, red blood cell and plate count remainedstable with Immediate release naltrexone.

Treatment of advanced pancreatic cancer with Opioid Growth Factor in 24patients Clinical benefit response was experienced by 53% of OGF-treatedpatients compared to historical controls of 23.8% and 4.8% forgemcitabine and 5-fluorouracil (5-FU), respectively. Of the subjectssurviving more than eight weeks, 62% showed either a decrease orstabilization in tumor size by computed tomography. The median survivaltime for OGF-treated patients was three times that of untreated patients(65.5 versus 21 days, p<0.001). No adverse effects on hematologic orchemistry parameters were noted, and quality of life surveys suggestedimprovement with OGF. This trial shows that Immediate release naltrexonecan slow or cause cell death.

A 46-year-old man diagnosed in October 2002, with poorly differentiatedadenocarcinoma of the pancreas with metastases to the liver, beganintravenous treatment with α-lipoic acid (ALA) 300 to 600 mg two timesper week, 4.5 mg Immediate release naltrexone (LDN) once per day atbedtime, oral ALA (600 mg/day), selenium (200 μg two times per day), andsilymarin (300 mg four times a day), including a strict dietary regimenalong with a stress-reduction and exercise program. The average lengthof survival after diagnosis of pancreatic cancer ranges from 3 to 6months; however this patient, at the time this article was written in2006 showed comparatively stable disease for more than a 3-year periodand an improved quality of life (Berkson et al., 2006).

A 61-year old man was diagnosed with biopsy-proven Follicular Lymphoma(FL). His initial physical examination and PET/CT scan showed multiplelarge, metabolically active, pathologic lymph nodes. After 6 months ofreceiving Immediate release naltrexone (LDN) daily in the evening, inaddition to a prescribed healthy diet, a nutritional supplement regimen,and intravenous α-lipoic acid (ALA). This patient however, did notremain compliant with the diet, the nutritional supplement, or the ALA.Thus the achievement of clinical and radiological remission was deemedto be due to the IMMEDIATE RELEASE NALTREXONE (LDN) alone. In 2007 whenthis report was published, per telephone communication from thepatient's wife, the patient remains asymptomatic from his disease, 1year after his last CT/PET imaging (Berkson et al., 2007).

Three patients presented to the same clinic and were all treated withthe same ALA+ Immediate release naltrexone (LDN) protocol. The patientspresented with the following diseases and had the following outcomes:Adenocarcinoma of the pancreas with metastases to the liver. Thispatient is alive and well 39 months after presentation of disease andinitiation of ALA+ Immediate release naltrexone (LDN) therapy.Adenocarcinoma of the pancreas with metastases to the liver, presentedwith the same diagnosis as the above patient. After 5 months of ALA+Immediate release naltrexone (LDN) therapy, a PET scan demonstrated noevidence of disease.

Pancreatic cancer with liver and retroperitoneal metastases, with ahistory of B-cell lymphoma and prostate adenocarcinoma. After 4 monthsof ALA+ Immediate release naltrexone (LDN) therapy his PET scandemonstrated no signs of cancer (Berkson et al., 2009).

Two Case Studies: Hepatoblastoma is the most common liver malignancy inchildren, typically diagnosed before age 2. The survival rate forhepatoblastoma has increased dramatically in the last 30 years, but thetypical chemotherapeutic agents used for treatment are associated withsignificant toxicity. In this report, the authors present two cases ofhepatoblastoma treated with surgical resection and a novelbiotherapeutic regimen that included opioid growth factor (OGF). Case #1is an infant diagnosed with a large mass on prenatal ultrasound. Aftersubsequent diagnosis of hepatoblastoma, she was treated with one courseof neoadjuvant chemotherapy at approximately 1 week of age. Followingsignificant complications from the chemotherapy (neutropenic fever,pneumonia and sepsis), the patient's parents declined furtherchemotherapy, and the infant was treated with surgical resection andopioid growth factor (OGF)/Immediate release naltrexone. She iscurrently at close to 10 years disease-free survival. Case #2 is a childdiagnosed with a liver mass on ultrasound at 20 months of age, laterbiopsy-proven to represent hepatoblastoma. Due to existingco-morbidities including autosomal recessive polycystic kidney diseaseand hypertension, and indications from the biopsy that the tumor mightbe insensitive to chemotherapy, the parents elected not to proceed withneoadjuvant chemotherapy. The patient was treated with surgicalresection and OGF/IMMEDIATE RELEASE NALTREXONE (LDN), and is currentlyat more than 5 years disease-free survival. This case series highlightsthe need for less toxic treatment options than conventionalchemotherapy. Modulation of the OGF-OGF receptor axis represents apromising safe and therapeutic avenue for effective treatment ofhepatoblastoma. Rogosnitzky M, Finegold M J, McLaughlin P J, Zagon I S.Invest New Drugs. 2013 August; 31(4): 1066-70.

85-year-old man diagnosed with stage 3-stomach cancer prognosis 6 monthsto live on Mar. 15, 2007 and started Immediate release naltrexone 4.5 mgon Mar. 28, 2007. In addition to Immediate release naltrexone patientsreceived chemotherapy and kidney stents inserted. Immediate releasenaltrexone was started after two rounds of chemotherapy in September2007 patient had a CT scan, that showed tumors shrunk in half andremoved the kidney stents. In December of 2007 patients was determinedto be in remission and stable. In March 2008 another CT scan was doneand tumors had shrunk in half, and a third scan was done in March of2009 and tumors were stable. Patients from 2007 through 2009 continuedon 4.5 mg of Immediate release naltrexone.

75 year old woman diagnosed with stage 4 pleural mesothelioma inDecember of 2008 and patients after consult with two other doctors itwas determined due to the state of the diseases and other health issuesto watch the tumors and not do chemotherapy. Prognosis was 6 to 12months. Patient started 4.5 mg nightly and received on other treatmentbut did change diet. Two CAT scans February 2009 and 2010 both showed nomeasurable growth of tumors. Immediate release naltrexone between 0.01mg and 10 mg has been shown to stabilize or show the growth of tumors.

A 69 year old man diagnosed with stage 4-colon cancer, 2007 which hadspread to his lungs and liver, they removed 40% of his colon and began around of chemotherapy and three surgeries removed 40% of his colon, halfis his right lung and 75% of his liver. During the next 18 monthsreceived 47 weeks of chemotherapy (a combination of 4 chemo drugs atonce). Was going to stop chemotherapy due to toxic side-effects butstarted IMMEDIATE RELEASE NALTREXONE in June of 2007 he started 4.5 mgnightly of IMMEDIATE RELEASE NALTREXONE immediately and was able tocomplete the entire protocol without any major side effects at all.Patient had scans every six months and continued cancer free until Juneof 2015 when they found a small growth in his right lung which theyremoved with no need for chemotherapy or radiation.

87 years old male was diagnosed with stage 3 prostate cancer which hewas originally treated for 5 years before began 3 rounds of Docetaxel(Taxotere®). He was prescribed 4.5 mg of IMMEDIATE RELEASE NALTREXONEwhich he took nightly and has continued with since the completion of theprotocol. Patient was able to withstand the chemotherapy and his bloodwork stayed stable throughout the protocol, and maintained his weight,and overall quality of life was much better.

Parkinson Disease

A eight-week clinical study in which 48 PD patients diagnosed with oneor more ICDs that developed during PD and in the context of dopamineagonist (DA) treatment will receive either naltrexone or placebotreatment in a blinded fashion. Recruitment will be such that all fourcommon ICDs in PD (compulsive gambling, buying, sexual behavior andeating) are equally represented. Patients will be seen every other weekduring the course of the study, and treatment response and tolerabilitywill be assessed at each visit.

The results of this study were negative for the efficacy of Immediaterelease naltrexone at 4.5 mg for the treatment of impulse controlsdisorders (such as compulsive gambling, buying, sexual behavior andeating) in Parkinson's disease (PD) using a clinician rating of generalimprovement, which was the primary outcome measure for the study.However, using a patient-completed, PD-specific assessment of impulsecontrol disorder symptom severity, naltrexone treatment was associatedwith a significant decrease in symptoms compared with placebo treatment.The results of this preliminary study support further research withnaltrexone for the treatment of these disorders in PD.

A 63 year old woman diagnosed with Parkinson disease in October 2008during the next three years doctors prescribed Sinemet, Requip causedmajor side effects, falling asleep while driving, and Symmetrel had tostop work, while they helped offer relief from her symptoms. In June of2011 patient started on 4.5 mg of IMMEDIATE RELEASE NALTREXONE and overthe next 6 month was able to titrate off all other medications and themajority of patient's symptoms have subsided.

A 72 year old male diagnosed with Parkinson Disease in October 2009suffered brain fog, shaking on right hand, very tired started 3 mg ofIMMEDIATE RELEASE NALTREXONE in August of 2013 as none of the standardtreatments were not helping or the side effects were not acceptable.Patient continues on IMMEDIATE RELEASE NALTREXONE today as his onlytreatment patients confirms brain fog gone and shaking is less.

A 66 year old male diagnosed with Parkinson Disease in November of 2011,patient suffered from hand/arm tremors, jaw/tongue tremors, memoryimpairment, lack of cognitive function, sleep disorder mask likeappearance, patient started on 1.5 mg of IMMEDIATE RELEASE NALTREXONEtitrating up to 3 mg. Major improvement within first 2weeks at 1.5 mgjaw/tongue tremors stopped and by 2nd month at 3 mg patients sats mentalfunction restore, hand/arm tremors have lessened and patient hasreturned to work patient takes on PD medications and continues onIMMEDIATE RELEASE NALTREXONE.

Autism

155 children participated in 10 studies; 27 received placebo. Of the 128that received naltrexone 98 (77%) showed statistically significantimprovement in symptoms of irritability and hyperactivity. Side effectswere mild and the drug was generally well tolerated.

Randomized, double blind, placebo-controlled study with Immediaterelease naltrexone in the treatment of autism. Eight of 13 subjectsimproved in two or more settings. Changes in parent measures (CGI,Conners Impulsivity-Hyperactivity Factor, and SE-Restlessness) andTeacher CGI achieved statistical significance. Teacher SE-Restlessnessand initiation of communication in the clinic showed a trend towardimprovement. Actometer readings improved in two children who were veryactive at baseline.

Opioid-immune interactions in autism: behavioral and immunologicalassessment during a double-blind treatment with naltrexone. Thebehavioral improvement was accompanied by alterations in thedistribution of the major lymphocyte subsets, with a significantincrease of the T-helper-inducers (CD4+CD8−) and a significant reductionof the T-cytotoxic-suppressor (CD4−CD8+) resulting in a normalization ofthe CD4/CD8 ratio. Changes in natural killer cells and activity wereinversely related to plasma beta-endorphin levels. It is suggested thatthe mechanisms underlying opioid-immune interactions are altered in thispopulation of autistic children and that an immunological screening mayhave prognostic value for the pharmacological therapy with opiate.

9 year old boy diagnosed with Autism & ADHD in June of 2007 no eyecontact and chronic stomach pain started IMMEDIATE RELEASE NALTREXONE in2009 started at 0.1 mg for 2 weeks then 2 mg 2 weeks 3 mg more TICS formonth as on Ritaline, Risperdal, Dexamine, today only takes IMMEDIATERELEASE NALTREXONE good eye contact and almost on pain.

4 year old girl diagnosed with Autism in 2008 was continually sickstarted IMMEDIATE RELEASE NALTREXONE in October 2009 side effect alittle constipation 5 ml at bedtime celxia and have continued celxiaplus IMMEDIATE RELEASE NALTREXONE has not been sick since startingIMMEDIATE RELEASE NALTREXONE and language skills have improved. This isimportant as many children with Autism suffer from IBS.

5 year old boy diagnosed with Autism in 2007 with autoimmune problems,very low NK activity, started IMMEDIATE RELEASE NALTREXONE 3 mg inAugust of 2009, hyperactivity increased for the first three weeks. Overthe next months social behaviors skyrocketed after IMMEDIATE RELEASENALTREXONE. Started requesting “play dates” with friends when that hadnever been a desire before. Developed real friendships after startingIMMEDIATE RELEASE NALTREXONE in addition to IMMEDIATE RELEASE NALTREXONEhe takes Nystatin, Fluconazole and supplements continues takingIMMEDIATE RELEASE NALTREXONE today

Autoimmune Hepatitis

Hepatic Methionine-enkephalin may interfere with response to antiviraltherapy in chronic hepatitis sought to investigate the expression of theimmunoreactivities of Met-enkephalin and of the δ-opioid receptor 1(DOR1), to which Met-enkephalin binds, preferentially, in liver samplesfrom 23 patients with chronic hepatitis C who had undergone antiviraltherapy. Twelve patients obtained a sustained virological response, and11 patients were relapsers after or nonresponders to treatment. Amongthe 12 patients with sustained virological response, one patient (8.3%)expressed MEIR and another one expressed DOR1 immunoreactivity (8.3%),whereas none of the patients expressed both immunoreactivities. Amongthe group of nonresponders/relapsers, one patient expressed MEIR (9%),two patients expressed DOR1 immunoreactivity (18.2%), and seven patientsexpressed both (63.6%). The difference between responders andnonresponders in the expression of both immunoreactivities wassignificantly different (P<0.001).

A 63 year old woman diagnosed January of 2012 with Hepatitis C andDiabetes started taking IMMEDIATE RELEASE NALTREXONE January 2013 4 mgonce a day in the morning. Was being controlled by Prednisone but washaving increasing side effects, and decided to try IMMEDIATE RELEASENALTREXONE. Patient no longer takes prednisone or other immunosupressiondrugs, continues to take 4 mg in morning

A 63-year-old female diagnosed with Autoimmune Hepatitis—Type 1 Novemberof 2008 was taking Prednisone, Azathioprine, and 6MP, Cellcept,Budesonide. Patients was having Liver function tests monthly and theywere elevated and rising monthly. Patient had vivid dreams and mildindigestion in the first two weeks. Patients for the first year hadmonthly blood tests hepatitis is under control with only 4.5 mgIMMEDIATE RELEASE NALTREXONE nightly

A 57 year old male diagnosed with Hepatitis C October 2002 patientssuffered from fatty liver, chronic hepatitis C, elevated liver enzymes,sever fatigue, IBD and Fibromyalgia and was treated with a number ofdifferent immunosupression drugs including prednisone, Patient startedIMMEDIATE RELEASE NALTREXONE in February of 2009 and stopped all othermedication and recent ultrasound shown No fatty liver, Liver enzymesdropped to normal, HCV viral load dropped from over a million in January2009 to 49,000 in May 2009. In May 2010, it had dropped down to 11.400.Patient continues to be stable has more energy, IBS is no longer aproblem and fibromyalgia is greatly improved.

A 6 year old girl diagnosed with Hepatitis B failed standard treatmentstarted 1 mg Immediate release IMMEDIATE RELEASE NALTREXONE within onemonth viral load decreased from 59.2 million to 53,000, ALT/ASTdecreased to normal. Within 7 months Sero-conversion to negativeantigens and positive antibodies, Viral load 551 additional benefitsincluded resolutions of eczema.

A 52 year old man diagnosed with Hepatitis C & stage 4 cirrhosis of theliver after one year of intensive alpha lipoic acid, glutathionetherapy, liver enzyme levels normal, Viral load still high and patienton transplant list Started Immediate release IMMEDIATE RELEASENALTREXONE 4.5 mg March of 2011 Viral load dropped from 24.4 million to11.9 million by May of 2011 by August of 2011 viral load dropped to 8.3million and has continued to drop through 2012

Blepharitis

62-year-old male diagnosed with blepharitis at age 45 was treated withvarious drugs including Antibiotic ointment and Restasi. Patient begantreatment with 3 mg of IMMEDIATE RELEASE NALTREXONE February of 2014 andrealized that his blepharitis has been cured for the first time in manyyears.

Complex Regional Pain Syndrome (CRPS)

A 48 year-old male veteran sustained an injury to his right leg in 2006.While undergoing aqua-therapy, he injured his right great toe, whichsubsequently became infected. Following drainage of an abscess andremoval of the great toe's nail, the patient developed the followingCRPS symptoms in his right lower extremity: swelling, allodynia (pain tonormal touch), color change, temperature change, and some weakness. By2007, the patient developed moderate CRPS symptoms in his upperextremities. In 2008, he developed blisters and skin ulceration in hisright lower extremity (FIG. 1). At this time, the patient was beingtreated with opioids, pregabalin, and duloxetine. By 2009, the patient'spain had become severe enough that he could not ambulate withoutassistance. He developed muscle spasms in the right upper extremity. In2010, he underwent a cardiac bypass surgery for coronary artery disease.His CRPS symptoms became widespread after this surgery, spreading to hisupper chest, upper arms, and forearms. In 2011, the patient developedsignificant dystonic spasms to both upper extremities, resulting inhyperextension of his fingers. From 2008 to 2012, the patient underwentmultiple treatments with anticonvulsants, antidepressants, physicaltherapy, psychotherapy, topical and systemic analgesics, including butnot limited to opioids. The patient also currently has diabetes mellitustype II, hypertension, hyperlipidemia, as well as coronary arterydisease.

In August of 2011, the patient began low-dose intravenous ketamineinfusions. He reported a good initial response, but the relief was notsustained. He continued to have ketamine booster infusions at intervalsof 4 to 6 weeks. Although the patient engaged in aggressive physicaltherapy during this time, his maximum interval of relief from painfollowing a given ketamine infusion decreased to an interval of 3 weeks.In January 2012, his use of the opioid oxycodone was changed totapentadol. This narcotic was removed for 1 week prior to startinglow-dose naltrexone, which was started and maintained at 4.5 mg per day(1 dose at night). Additional medications included: metformin, tramadol,valsartan, cloazepate, simvastatin, fish oil, and vitamin C. Immediatelybefore IMMEDIATE RELEASE NALTREXONE treatment, the patient had patchyareas of allodynia to the medial and dorsal aspect of his right foot,extensive areas of dysesthesia in his right lower extremity below theknee and heel of his foot, as well as bilaterally dysesthesia in theupper extremities. There were significant color and temperature changesin the right foot compared to the left foot, as well as pitting edema inthe right foot. A triple-phase bone scan revealed significant reuptakein the right foot, characteristic of CRPS. By March of 2012, thepatient's requirements for the lower dose intravenous ketamine infusionswere not as frequent (6 week intervals, pain spikes not as high). Thepatient recovered from CRPS flares more quickly, felt more energetic,and tolerated pain better. He became physically more active, and hissleep improved significantly. Within 2 months after starting IMMEDIATERELEASE NALTREXONE, the patient's dystonic spasms discontinued, althoughhe still had moderate pain in both upper extremities. The patient wasable to walk without a cane (FIG. 2b), which he had used continuouslysince 2006. His pain was an average of 8 to 10 on the Numeric RatingScale (NRS) before starting IMMEDIATE RELEASE NALTREXONE. It droppeddown to an average of 5 to 6 on the NRS after starting IMMEDIATE RELEASENALTREXONE. After IMMEDIATE RELEASE NALTREXONE therapy, the patient'spain symptoms have reduced in severity, but not in their distribution.His current mood state is good. No side effects of IMMEDIATE RELEASENALTREXONE were noted.

A female patient, currently 12 years old, has a genetic disorder,Ehlers-Danlos Syndrome (EDS) hypermobility type 1, dysautonomia,non-epileptic seizures, chronic gastritis, mitochondrial dysfunction,asthma, vision loss, thyroid tumor and anti-cardiolipin antibodies. As aresult of her EDS, the patient has had repeated dislocations of herright shoulder, as well as her right ankle. The patient first developedCRPS in her lower right extremity in 2008. In 2009, the patientdeveloped dystonic muscle spasms in the upper extremities, which wereinterpreted by her physicians as evidence of a conversion disorder. Thepatient was first seen by one of us (PC) in February of 2011. Hersymptoms of CRPS included color change, increased temperature in theright foot (90° C.) versus (82° C.) in the left foot, allodynia over thedorsum of right foot, and patchy areas of dysesthesia over her rightleg. She also had areas of allodynia and dysesthesia in the left lowerextremity and both upper extremities, as well as distorted nails on theright foot. When first seen, the patient's medications werelevetiracetam, midodrine, baclofen, trazodone, diphenhydramine,lansoprazole, budesonide, levalbuterol, L-Carnitine, coenzyme Q10,vitamin D, vitamin C, magnesium, and vitamin B complex. She rated herpain on a NRS (Numerical Rating Scale) as 8/10 at its lowest and 10/10at its worst. In early 2011, the patient experienced a subluxation ofher right ankle. The lower right leg and ankle subsequently developedfixed dystonia, with plantar flexion and varus. Fixed dystonia,allodynia, and vasomotor abnormalities in the right lower extremity of aCRPS patient (panel a) remitted following treatment with a low-dosenaltrexone. No symptoms and signs of CRPS after IMMEDIATE RELEASENALTREXONE treatment. Two months after surgical reinforcement of theright ankle for Ehlers-Danlos Syndrome (EDS) In June 2011, the patientwas started on low dose naltrexone (IMMEDIATE RELEASE NALTREXONE) of 3mg once a day and ketamine troches (sublingual) 10 mg on as neededbasis. The IMMEDIATE RELEASE NALTREXONE was increased to 4.5 mg per day,4 weeks after starting it. IMMEDIATE RELEASE NALTREXONE was started as alower dose to gauge tolerability. She tolerated the IMMEDIATE RELEASENALTREXONE very well with no reports of adverse effects. Her pain scoresdropped from NRS (7-10)/10, to (3-5)/10. She also reported a decrease inallodynia, as well as a decrease in sensitivity to touch and temperaturechange. There was no effect on the dystonia. Two months after startingIMMEDIATE RELEASE NALTREXONE, she underwent 400 units of botulinumtoxin, injections to the right gastrocnemius group of muscles withminimal relief of her dystonia. The right lower extremity was placed inan above knee cast for 6 weeks. Several weeks after the cast wasremoved, the patient subluxated her right ankle again. She underwent a400 units injection of botulinum toxin, and a cast was applied again.The patient used ketamine troches (10 mg) for 3 weeks after theIMMEDIATE RELEASE NALTREXONE was started, as needed for pain. She wastaking ketamine troches on as needed basis for acute flare-ups of herCRPS pain. This was limited to no more than 30 mg of ketamine trochesper day. The patient progressively reduced her use of ketamine troches 3weeks after starting IMMEDIATE RELEASE NALTREXONE, and by 8 weeks wastaking them rarely. In December of 2011, she underwent percutaneouspinning of the right ankle to stabilize the joint. The pins were removed6 weeks later and the ankle joint subluxated again. In February of 2012,the patient underwent reinforcement to the right ankle with cadaverligaments. She continued to be on low dose naltrexone during this time,except for 4 perioperative days, during which the IMMEDIATE RELEASENALTREXONE was discontinued. As per institutional protocol, IMMEDIATERELEASE NALTREXONE was stopped for 24 h before surgery. After surgery,she was given oral opioids (hydrocodone with acetaminophen) for 1 week.The oral opioids were then discontinued, and IMMEDIATE RELEASENALTREXONE treatment was resumed 24 h, after her last dose of opioid.The patient noticed a decrease in her post-operative pain, ranging from(4-6)/10, 3 weeks after resuming IMMEDIATE RELEASE NALTREXONE. Skindiscoloration and allodynia could not be assessed after the surgerybecause her leg was in a cast. At the time of cast removal, thepatient's lower leg and ankle had a normal range of motion, indicating aremission of the leg's fixed dystonia (FIG. 3b). The leg had a slightred color at the time of cast removal, but no allodynia. Ten monthsafter surgery, the patient's gait was normal. Remarkably, the patientdid not experience any spread of her CRPS, despite undergoing multipleinvasive procedures, including surgery. One of the known triggers for aCRPS flare-up, or spread of CRPS symptoms, is trauma (Schwartzman et al.2009; van Rijn et al. 2011). The patient still has a chronic shoulderdislocation, associated with her EDS. However, her CRPS symptoms haveresolved completely. The patient has been maintained on IMMEDIATERELEASE NALTREXONE for 18 months. No side effects of IMMEDIATE RELEASENALTREXONE have been noted.

Crohn's Disease

A pilot clinical trial was conducted in children with moderate to severeCrohn's disease. Fourteen subjects with a mean age of 12.3 years (range,8 to 17 y) were enrolled. Children were randomized to placebo orImmediate release naltrexone (0.1 mg/kg) orally for 8 weeks followed byopen-labeled treatment with 8 additional weeks of naltrexone. Safety andtoxicity were monitored by physical examinations and blood chemistries.Clinical activity was assessed by the Pediatric Crohn's Disease ActivityIndex (PCDAI) and Quality of life was monitored by the Impact IIIsurvey. Oral Immediate release naltrexone was well tolerated without anyserious adverse events in children with moderate to severe Crohn'sdisease. PCDAI scores significantly decreased from pretreatment values(34.2±3.3) with an 8-week course of naltrexone therapy (21.7±3.9)(P=0.005). Twenty-five percent of those treated with naltrexone wereconsidered in remission (score≤10) and 67% had improved with milddisease activity (decrease in PCDAI score by at least 10 points) at theend of the study. Systemic and social quality of life improved withnaltrexone treatment (P=0.035).

Eligible subjects with histologically and endoscopically confirmedactive Crohn's disease activity index (CDAI) score of 220-450 wereenrolled in a study using 4.5 mg naltrexone/day. Infliximab was notallowed for a minimum of 8 weeks prior to study initiation. Othertherapy for Crohn's disease that was at a stable dose for 4 weeks priorto enrollment was continued at the same doses. Patients completed theinflammatory bowel disease questionnaire (IBDQ) and the short-form(SF-36) quality of life surveys and CDAI scores were assessedpretreatment, every 4 weeks on therapy and 4 weeks after completion ofthe study drug. Drug was administered by mouth each evening for a12-week period. RESULTS: Seventeen patients with a mean CDAI score of356+/−27 were enrolled. CDAI scores decreased significantly (P=0.01)with LDN, and remained lower than baseline 4 weeks after completingtherapy. Eighty-nine percent of patients exhibited a response to therapyand 67% achieved a remission (P<0.001). Improvement was recorded in bothquality of life surveys with LDN compared with baseline.

No laboratory abnormalities were noted.

Forty subjects with active Crohn's disease were enrolled in the study.Randomized patients received daily oral administration of 4.5-mgnaltrexone or placebo. Providers and patients were masked to treatmentassignment. The primary outcome was the proportion of subjects in eacharm with a 70-point decline in Crohn's Disease Activity Index score(CDAI). The secondary outcome included mucosal healing based uponcolonoscopy appearance and histology. Eighty-eight percent of thosetreated with naltrexone had at least a 70-point decline in CDAI scorescompared to 40% of placebo-treated patients (p=0.009). After 12 weeks,78% of subjects treated with naltrexone exhibited an endoscopic responseas indicated by a 5-point decline in the Crohn's disease endoscopy indexseverity score (CDEIS) from baseline compared to 28% response inplacebo-treated controls (p=0.008), and 33% achieved remission with aCDEIS score<6, whereas only 8% of those on placebo showed the samechange. Fatigue was the only side effect reported that was significantlygreater in subjects receiving placebo.

Forty-two IBS patients participated in an open-label study. Participantsreceived 0.5 mg PTI-901/day for 4 weeks and were evaluated duringbaseline, during treatment, and at 4-week follow-up. Patients recordeddegree of abdominal pain, stool urgency, consistency, and frequency.Primary outcomes were number of pain-free days and overall symptomrelief, evaluated by a global assessment score. Data were analyzed perprotocol. Global assessment improved in 76% of 42 patients. Duringtreatment, the mean weekly number of pain-free days increased from0.5+/−1 to 1.25+/−2.14 (P=0.011). There were no significant adversereactions. PTI-901 improves pain and overall feeling, and is welltolerated by IBS patients.

Diabetic Neuropathy

63-year-old male, diagnosed with diabetic neuropathy for the last sixyears was prescribed one or two tablets every four to six hours asneeded for pain. Patient takes between 4 to 8 tablets a day. Started 4.5mg of IMMEDIATE RELEASE NALTREXONE in March of 2015 and within 3 dayswas able to cut down the number of pills in half within 8 weeks patientstopped all pain medication, additional benefits included resolutions ofRLS.

Fibromyalgia

Thirty-one women with fibromyalgia participated in the randomized,double blind, placebo-controlled, and counterbalanced, crossover study.During the active drug phase, participants received 4.5 mg of oralnaltrexone daily. An intensive longitudinal design was used to measuredaily levels of pain. When contrasting the condition end points, weobserved a significantly greater reduction of baseline pain in thosetaking low-dose naltrexone than in those taking placebo (28.8% reductionversus 18.0% reduction; P=0.016). Low-dose naltrexone was alsoassociated with improved general satisfaction with life (P=0.045) andwith improved mood (P=0.039), but not improved fatigue or sleep.Thirty-two percent of participants met the criteria for response(defined as a significant reduction in pain plus a significant reductionin either fatigue or sleep problems) during low-dose naltrexone therapy,as contrasted with an 11% response rate during placebo therapy (P=0.05).Low-dose naltrexone was rated equally tolerable as placebo, and noserious side effects were reported.

Ten women meeting criteria for fibromyalgia and not taking an opioidmedication were dosed with Immediate release Naltrexone, in addition toantagonizing opioid receptors on neurons, also inhibits microgliaactivity in the central nervous system. At doses (4.5 mg), Immediaterelease naltrexone may inhibit the activity of microglia and reversecentral and peripheral inflammation. The results showed that Immediaterelease naltrexone at 4.5 mg reduced fibromyalgia symptoms in the entirecohort, with a greater than 30% reduction of symptoms over placebo. Inaddition, laboratory visits showed that mechanical and heat painthresholds were improved by the drug. Side effects (including insomniaand vivid dreams) were rare, and described as minor and transient.Baseline erythrocyte sedimentation rate predicted over 80% of thevariance in drug response. Individuals with higher sedimentation rates(indicating general inflammatory processes) had the greatest reductionof symptoms in response to Immediate release low-dose naltrexone. Whichconfirms the ability of Immediate release naltrexone to decree pain andinflammation.

Hashimoto's Thyroiditis

A 45-year-old woman diagnosed with Hashimoto's Mar. 10, 2019 Low energy,nerve pain, development of metabolic syndrome (insulin resistance),folliculitis that had not healed after 4 months, even after 28 days onan oral antibiotic, reduction in T3 hormone levels (which caused me toswitch from synthroid to Nature Throid in order to optimize levels of T4and T3 hormones). Started IMMEDIATE RELEASE NALTREXONE 1.5 mg January of2015. Prior to starting IMMEDIATE RELEASE NALTREXONE patient was takingAdvair, Nasacort, Albuterol, in addition to thyroid hormone, zyrtec,omeprazole, atorvastatin, metformin, and several supplements. Afterstarting IMMEDIATE RELEASE NALTREXONE, patient was able to go off theAdvair, Nasacort, and Albuterol. Patients stated sleep quality hasimproved, energy levels have increased, and allergy symptoms havedramatically decreased, and has not suffered from asthma attacks sincestarting. No longer has pins-and-needles pain in her feet anymore, andthe folliculitis finally healed after taking IMMEDIATE RELEASENALTREXONE for a few weeks. Latest lab work was normal in all areas.

A 40 year old man was diagnosed October 2011 with Hashimoto Thyroiditis,but believes that his auto-immune disease has progressed and stated overthe last 2 years has battled Insomnia, extreme fatigue, bed bound formonths at a time, anger, severe depression, brain fog, irritability andneck & back-muscle pain, and no longer responded to synthetic hormonelike L-Thyroxin and Euthyrox. Started 1.5 mg of IMMEDIATE RELEASENALTREXONE for 2 months then 3 mg and continues on 3 mg in morning and 1mg at night side effect strange dreams. It took weeks to get my energyback and for the depression to go away. Patient was taking L-thyroxineand pain medications and 75 mg Zoloft. Patient is off all medicationaccept IMMEDIATE RELEASE NALTREXONE and back at work.

A 50 year old woman diagnosed with hyopthyroid since 1992, and diagnosedJuly 2013 Hashimoto's, MTHFR, adrenal fatigue, estrogen dominance, lowB12, low D Patients started at 1.5 mg for 2 weeks then 3 mg for 4 weeksand 4.5 mg and continues on IMMEDIATE RELEASE NALTREXONE today. Patientswas taking Synthroid 150 mcg, Compounded T3 25 mcg, Progesterone 150 mg,Plus lots of supplements like Magnesium, D3, Methyl B12, Methyl folate,Selenium, E, Amino Restore, CLA, NAC, DE, Adaptacin. Patients states shehas regained energy, stamina, and am gaining my strength back, chronic13 yr hip pain in very minimal, ear discharge stopped and gums do notbleed, Neck pain is gone, has stopped pain pills, TgAb lowered from 77to <1, TPO lowered from 229 to 203. Patient continues on 4.5 mgIMMEDIATE RELEASE NALTREXONE has stopped T3, decreased Synthroid from150 to 50 and B12 went from 300 to 1785 after starting IMMEDIATE RELEASENALTREXONE and IMMEDIATE RELEASE NALTREXONE helped my absorption issuesand conversion of T4 to T3.

A 39-year-old woman diagnosed with Hashimoto's her TPO levels were 350when initiated T3/T4/19 mcg capsules and Immediate release IMMEDIATERELEASE NALTREXONE 4.5 mg in August 2011. Patients TPO levels returnedto normal and patient reduced T3 to 2.25 mg and continues on 4.5 mg ofIMMEDIATE RELEASE NALTREXONE

Shingles, or Herpes Zoster

A 45-year-old woman diagnosed with Shingles in 2010 over 18 months had 8major outbreaks, and was treated with acyclovir, and valacyclovir, asthe outbreaks continued they prescribed Lidocaine patches and painmedications. In order to help reduce the pain and the duration ofshingles, Started 4.5 mg of IMMEDIATE RELEASE NALTREXONE nightly in 2013and have not had a single outbreak, additional benefit have not evengotten a cold

Inflammatory Bowel Disease

A 16 year old boy diagnosed with Ulcerative Colitis in 2007 patient whenfirst seen had lost 30 lb. and anemic, and surgery was beingrecommended, school attendance was sporadic. Patients was prescribedRemicade and GI specialists wanted to increase the dose and frequency oftreatments. In May of 2007 patient started a high corroborate dietprotocol and 4.5 mg of IMMEDIATE RELEASE NALTREXONE at bedtime over thenext five months patient gained 4.5 mg IMMEDIATE RELEASE NALTREXONE,returned to school with attendance 100 percent, first time since in twoyears he was able to run track and cross-country without missing anevent. Patient continues on diet protocol plus 4.5 mg of IMMEDIATERELEASE NALTREXONE

Myasthenia Gravis

A 68 year old woman has suffered with myasthenia gravis for over 20years with effect on her eyesight, chewing, swallowing and. Weakness andnumbness of both legs and arms. Patient started IMMEDIATE RELEASENALTREXONE at 4.5 mg per day at bedtime. Over the next 3 weeks hereyesight began to improve as well as the here other symptoms and herdoctors said she was symptom free first time in over 20 years. Patienttraveled out of the US and ran out of her IMMEDIATE RELEASE NALTREXONEand her symptoms began to return within 72 hours the worst was thedouble vision and muscle weakness. When she returned to the UnitedStates she immediately resumed her Immediate release naltrexonetreatment and has had no attacks since.

Multiple Sclerosis A Pilot Trial of Low-Dose Naltrexone in PrimaryProgressive Multiple Sclerosis

A sixth month phase II multicenter-pilot trial with a low dose of theopiate antagonist Naltrexone (LDN) has been carried out in 40 patientswith primary progressive multiple sclerosis (PPMS). The primary endpoints were safety and tolerability. Secondary outcomes were efficacy onspasticity, pain, fatigue, depression, and quality of life. Clinical andbiochemical evaluations were serially performed. Protein concentrationof beta-endorphins (BE) and mRNA levels and allelic variants of themu-opioid receptor gene (OPRM1) were analyzed. Results Five dropouts andtwo major adverse events occurred. The remaining adverse events did notinterfere with daily living. Neurological disability progressed in onlyone patient. A significant reduction of spasticity was measured at theend of the trial. BE concentration increased during the trial, but noassociation was found between OPRM1 variants and improvement ofspasticity. Our data clearly indicate that LDN is safe and welltolerated in patients with PPMS.

Pilot Trial on Low-Dose Naltrexone and Quality of Life in MultipleScleroses with 80 Patients:

To evaluate the efficacy of 4.5 mg nightly naltrexone on the quality oflife of multiple sclerosis (MS) patients. This single-center,double-masked, placebo-controlled, crossover study evaluated theefficacy of 8 weeks of treatment with 4.5 mg nightly naltrexone(low-dose naltrexone, LDN) on self-reported quality of life of MSpatients. RESULTS: Eighty subjects with clinically definite MS wereenrolled, and 60 subjects completed the trial. Ten withdrew beforecompleting the first trial period: 8 for personal reasons, 1 for anon-MS-related adverse event, and 1 for perceived benefit. Databasemanagement errors occurred in 4 other subjects, and quality of lifesurveys were incomplete in 6 subjects for unknown reasons. The high rateof subject dropout and data management errors substantially reduced thetrial's statistical power. LDN was well tolerated, and serious adverseevents did not occur. LDN was associated with significant improvement onthe following mental health quality of life measures: a 3.3-pointimprovement on the Mental Component Summary score of the Short Form-36General Health Survey (p=0.04), a 6-point improvement on the MentalHealth Inventory (p<0.01), a 1.6-point improvement on the Pain EffectsScale (p=0.04), and a 2.4-point improvement on the Perceived DeficitsQuestionnaire (p=0.05). LDN significantly improved mental health qualityof life indices. Further studies with LDN in MS are warranted.

Retrospective Chart Review of MS Patients Receiving Low Dose Naltrexone(LDN) to Assess Safety, Tolerability, and Effect on Fatigue.

This study investigated the safety, tolerability, and benefits (fatigue,reduction) of LDN in patients with MS. It reviewed the number ofpatients who stopped taking LDN and if there were specific reasons forstopping the LDN. The frequency and variety of side effects that werespecific to LDN use are reported._A retrospective review was performedon 435 charts of MS patients who were seen in the Penn State Hersheyout-patient Multiple Sclerosis Clinic between Jan. 1, 2005 and May 31,2012. There were 215 MS patients having exposure to LDN during the timeof this study._RESULTS: The study confirmed an improvement in quality oflife with the use of LDN over a long period of time. In addition to theassessment we review Brain MRIs and Spinal Cord MRIs that were obtainedas part of the clinical status of the patient and standard of care.

A 42-year-old woman with M.S. of four years was started on 1.5 mg ofImmediate release IMMEDIATE RELEASE NALTREXONE for two weeks thenincreased to 3 mg for two weeks and has been on IMMEDIATE RELEASENALTREXONE at 4.5 mg for seven months. Her M.S. is of the fastdeteriorating type with increasing weakness, spasticity andincoordination of her arms and legs with some cognitive abilitydeterioration apparent to her physicians-on each two months follow-upvisit. Over a number the last six months since starting the IMMEDIATERELEASE NALTREXONE, the disease has stabilized and the progressivedeterioration has stopped.

A 70-year-old woman one with M.S. of 35 years was started on 3 mg ofImmediate release IMMEDIATE RELEASE NALTREXONE for 30 days thenincreased to 4.5 mg and has taken IMMEDIATE RELEASE NALTREXONE for twoyears. Her M.S. has been of the slow deteriorating type with increasingweakness, spasticity and incoordination of her arms and legs withdeterioration of both eyesight and connectivity ability anddeterioration apparent to her physicians on each six-month follow-upvisit. Patient was homebound and wheelchair bound at the time shestarted Immediate release IMMEDIATE RELEASE NALTREXONE at bedtime. Overthe next three months she regained her ability to see and walk and hercognitive ability improved as well, the disease has stabilized and theprogressive deterioration has stopped.

A 54-year-old man with MS of 8 years was started on 4.5 mg of Immediaterelease IMMEDIATE RELEASE NALTREXONE. Patients was diagnosed with wasrelapsing remitting M.S. in 2008 has been of the slow deteriorating typewith increasing weakness, spasticity and incoordination of his arms andlegs with both deteriorations apparent to his physician on each sixmonth follow up. Patient has been treated with Tysabri and Copaxone andthey were getting ready to change his medicine once again as it was nolonger effective so patient decided to begin treatment with Immediaterelease IMMEDIATE RELEASE NALTREXONE. Over the last two and a half yearssince starting the IMMEDIATE RELEASE NALTREXONE, the disease hasstabilized and the progressive deterioration has stopped and his lastMRI showed brain lesion healing.

A 49 year old woman diagnosed with Relapsing Remitting MS in June 1999,prescribed a number of medications from January 1999 through September20012 which included Avonex, Copaxone, Beta-Seron, Prednisone, 11 mgBaclofen twice a day from 1999-2001. In September of 2002 was prescribedTopamax 100 mg after patients suffered from 3 seizures. Patient wasprescribed 4.5 Immediate release IMMEDIATE RELEASE NALTREXONE withTopamax and patient continue both Topamax until 2006 at which timepatients discontinued the use of Topamax and continues with 4.5 mg ofIMMEDIATE RELEASE NALTREXONE taken at bedtime with Vitamin D one a dayand Firs oil. When patient started IMMEDIATE RELEASE NALTREXONE in 2002over the next few months few spams, increasing body strength, lessnumbness and tingling, fewer headaches. Patient has not had a onerelapse since starting IMMEDIATE RELEASE NALTREXONE and MRI over thelast 8 years showed no progression of the disease and continues of 4.5mg Immediate release IMMEDIATE RELEASE NALTREXONE.

A 33 year old woman diagnosed in 2001 Relapsing Remitting MS, andstarted on Avonex from 2002-mid 2003 with no major relapse. By Mid 2003relapses were more frequent and started on Reib January of 2004 patientswas laid off from her job due to MS symptoms that included poor balance,bladder problems, deteriorating vision and handwriting. Patient becamewheelchair bound in March of 2004 due to leg weakness. Patients originaldoctor refused to prescribe IMMEDIATE RELEASE NALTREXONE. Patient inJuly 2004 was prescribed IMMEDIATE RELEASE NALTREXONE 3 mg nightlywithin 3 days spams subsided and bladder urgency was reduced but all ofmy other MS related symptoms were improving. Patient was walking againwith a cane for assistance within 10 days of starting IMMEDIATE RELEASENALTREXONE. In August of 2004 IMMEDIATE RELEASE NALTREXONE was increasedto 4.5 mg nightly with minimal side effects some insomnia the 30 daysbut then subsided. Patient last update was 2010 and was still driving,living alone and have some balance issues no relapses continue to take4.5 mg nightly.

A 55-year-old male was diagnosed with Relapsing Remitting MS in 1998,and Secondary Progressive in 2002. Patient's chief symptoms extrememixed sleep apnea, chronic obstructive pulmonary diseases (COPD)inability to walk, total deafness in left ear and inability toconcentrate for any period of time. Patient prior to starting IMMEDIATERELEASE NALTREXONE was from February 1998-August 2001 Avonex, 1999 to2000 Copaxone and Avonex together; March 2002-June of 2005 Rebit andSeptember 2001 to 2002 Cytoxan (chemotherapy) August 2001 plasmaexchange for eleven days. From 2001-2005 multiple infusion of SolmefrolIV steroids (minimum of 4 times a year) Gabapentin 3 times a day,Clonazpam 1 time nightly, Effexor XR 2 times a day 37 mg, Acicept 1 timea day 11 mg, Flomax 1 time a day 11 mg Baclofen 3 times a day 10 MEQCAP, and Furosemide 1 time a day 40 mg. As of June of 2005 was on oxygen24/7, wheelchair bound, MS flairs one a month. Patient in July of 2005was prescribed 1.5 mg of IMMEDIATE RELEASE NALTREXONE one time a day atbedtime increasing to 3 mg of IMMEDIATE RELEASE NALTREXONE within 7 daysstopped taking Rebit, no real improvement in the first three monthsaccept no flair of MS. Patient improved slowly over the next 3 months,was able to take time off oxygen to extended periods of time, strengthreturned in in legs and arms and was able to take short walks withwalker, then longer walks then upgraded from wheelchair to cane. Sleepbegan to improve. At six month all my tests results improved. Patientscontinues to do well is driving and only taking 4.5 mg IMMEDIATE RELEASENALTREXONE and Vitamin D Supplements September 2012.

A 46 year old female, was diagnosed with relapsing remitting MS in 2002and managed the symptoms on a combination of MS drugs until 2010 whenshe was forced to go part time due difficulty with brain fog, severeinsomnia, severe fatigue and debilitating frequent exacerbations. Alsopoor sleep quality. Treatment Plan: January 2005 IMMEDIATE RELEASENALTREXONE 1.5 mg increasing to 4.5 mg nightly at bedtime. In additionto IMMEDIATE RELEASE NALTREXONE patient was prescribed bio-identicalprogesterone and estriol 8 mg, Cortef for adrenal support MS, response,Patient began sleeping better within 2 week, Energy levels improved andbrain fog, started to clear within a month, Exacerbations became lessfrequent and have stopped, patient returned to work within 12 months ofstarting the protocol patient has been back at work for 5 years withoutan exacerbation

A 54-year-old male diagnosed with secondary-progressive multiplesclerosis (SPMS) in 2006 current treatment included Tysabri infusionsdifficulty walking, severe heat sensitivity unable to work. In July of2009 patient started Immediate release IMMEDIATE RELEASE NALTREXONE at1.5 mg for one week to 3 mg in week two patient saw immediateimprovement increased stamina, was able to return to work, in January of2011 MRI showed reduced plaque and lesion size

This study investigated the safety, tolerability, and benefits (fatigue,reduction) of IMMEDIATE RELEASE NALTREXONE (LDN) in patients with MS. Itreviewed the number of patients who stopped taking IMMEDIATE RELEASENALTREXONE (LDN) and if there were specific reasons for stopping theIMMEDIATE RELEASE NALTREXONE (LDN). The frequency and variety of sideeffects that were specific to IMMEDIATE RELEASE NALTREXONE (LDN) use arereported. A retrospective review was performed on 435 charts of MSpatients who were seen in the Penn State Hershey out-patient MultipleSclerosis Clinic between Jan. 1, 2005 and May 31, 2012. There were 215MS patients having exposure to IMMEDIATE RELEASE NALTREXONE (LDN) duringthe time of this study. RESULTS: The study confirmed an improvement inquality of life with the use of IMMEDIATE RELEASE NALTREXONE (LDN) overa long period of time. In addition to the assessment we review BrainMRIs and Spinal Cord MRIs that were obtained as part of the clinicalstatus of the patient and standard of care. There were essentially noMRIs obtained immediately before IMMEDIATE RELEASE NALTREXONE (LDN) wasstarted as would have been ideal in a prospective study.

The average number of days of the Brain MRI before treatment withIMMEDIATE RELEASE NALTREXONE (LDN) was started was 444 days with amaximum of 4751 days. The average number of days to the latest Brain MRIafter IMMEDIATE RELEASE NALTREXONE (LDN) was started was 708 with amaximum of 1772 days of 215 patients on IMMEDIATE RELEASE NALTREXONE(LDN) 113 MRI scans showed stable, 14 showed improvement, 28 slightlyworse. The Slightly Worse MRI series indicated that new but inactivelesion(s) were identified when compared to the pretreatment study MRI.On the quality of life surveys showed 83 patients said they hadimproved, 92 patients said they were stable and 9 worse. The remainderof the patients did not continue on IMMEDIATE RELEASE NALTREXONE (LDN).

Psoriatic Arthritis

A 55 Year old man with psoriatic arthritis for 8 years and was beingtreated with Humira and was concerned about the side effects of the drugas he had been hospitalized four times over a 18 month period forPneumonia and kidney infections and decided to begin treatment withIMMEDIATE RELEASE NALTREXONE. He started on 4.5 mg of Immediate releaseIMMEDIATE RELEASE NALTREXONE fat bedtime. Within 10 days of startingIMMEDIATE RELEASE NALTREXONE he was able to discontinue all paidmedications as well as the Humira and over the last six months sincestarting the IMMEDIATE RELEASE NALTREXONE, the disease has stabilizedand the progressive deterioration has stopped.

Rheumatoid Arthritis (RA)

A 40 year old woman diagnosed with Rheumatoid Arthritis in 2006 and wasbeing treated with methotrexate and plaquenil but patients continuedwith pain and fatigue. In April of 2009 patients started treated with1.5 mg of Immediate release IMMEDIATE RELEASE NALTREXONE and titrated upto 4.5 mg over two months. Tried stopping methotrexate in July 2009starting have bad flares and again started methotrexate Successfullydiscontinued methotrexate March of 2010 and then discontinued plaquenilin October of 2010 patient continues on 4.5 mg of Immediate releaseIMMEDIATE RELEASE NALTREXONE.

Systemic Sclerosis (Scleroderma)

A 44 year old male diagnosed with Systemic Lupus by Rheumatologist in in2005 patient suffered from malar rash, Reynaud's Disease & ArthriticPain, difficulty with mobility multiple hospital admission since 2005fluid on the lungs and skin blister: began treatment of 3 mg ofIMMEDIATE RELEASE NALTREXONE March 2013 increasing to 4.5 mg in May of2013. Patient within three weeks after beginning treatment withIMMEDIATE RELEASE NALTREXONE had improved mobility, within 4 monthsjoints improved walking daily, skin cleared almost 100% blood resultsimproving. Patient before starting IMMEDIATE RELEASE NALTREXONE was onImuran 75 mg, treated with high dose steroids, and ace inhibitor,ramipril. Patients continues on take 4.5 mg of IMMEDIATE RELEASENALTREXONE and has had no hospital stays since March of 2013.

A 32 year old female diagnosed with systemic lupus with psoriasis, IBSand chronic fatigue develops joint pain, increasing abdominal pain andmalar rash Patient refused immunosuppressing drugs and tried supplementsand healthy diet ⋅ Patient contracted MRSA in 2010 in hospital ⋅ MRSAtreated with oral drugs twice, then with IV drugs patient developedsepsis. Infection kept recurring boils. ⋅ Antibiotics work, but patientcontinued to get sicker and sicker with worsening symptoms and risingANA although no organ damage.

Unable to take immunomodulating drugs due to MRSA recurrence andintolerant to others standard treatments for lupus, her doctors informedhere that they could offer no help and she needed to put her affairs inorder as it was only a matter or time. In 2012 office, she receives:HBO, acupuncture, supplement tailoring, treatment for mercury toxicity,food elimination diet then rotation, treatment for yeast overgrowth; ⋅She is started on IMMEDIATE RELEASE NALTREXONE 1.5 mg, but is unable totake it due to insomnia and pruritis. ⋅ IMMEDIATE RELEASE NALTREXONEchanged to liquid form and started at 0.5 mg, IMMEDIATE RELEASENALTREXONE decreased to 0.1 mg and increased by 0.1 mg once a week untilshe reached 1.5 mg, which is where she stays. Lupus, in remissioncurrently still on IMMEDIATE RELEASE NALTREXONE, supplements, healthydiet and lifestyle No recurrence of MRSA in 8 years No signs or symptomsof lupus and normal ANA for 7 years Intestinal symptoms resolved for 2years with some issues when patient does not stay on a healthy diet.Psoriasis mostly resolved.

Fibromyalgia

Twenty-five patients diagnosed with fibromyalgia treatment with(Immediate release naltrexone) LDN open label study carried out at asingle center Of the 22 patients completing the study, using 4.5 mgImmediate release naltrexone 7 (32%) remained on naltrexone monotherapythroughout the study. At Month 3, a 19.5% overall improvement in FIQRwas “The patients reported decreases in anxiety, pain, and sleepinghabits from baseline reported. Eleven patients (50%) had an average of a41% improvement in FIQR.

Double Blind Crossover to determine whether low dosages (4.5 mg/day) ofImmediate release naltrexone reduce fibromyalgia severity as comparedwith the nonspecific effects of placebo. When contrasting the conditionend points, we observed a significantly greater reduction of baselinepain in those taking low-dose naltrexone than in those taking placebo(28.8% reduction versus 18.0% reduction; P=0.016). Low-dose naltrexonewas also associated with improved general satisfaction with life(P=0.045) and with improved mood (P=0.039), but not improved fatigue orsleep. Thirty-two percent of participants met the criteria for response(defined as a significant reduction in pain plus a significant reductionin either fatigue or sleep problems) during low-dose naltrexone therapy,as contrasted with an 11% response rate during placebo therapy (P=0.05).Low-dose naltrexone was rated equally tolerable as placebo, and noserious side effects were reported.

A Woman aged 53 was diagnosed in 1998 Fibromyalgia and Epstein Barr, hadto quit work, in pain and very depressed. Various treatments over theyears for pain prescribed and other problems with the disease. Wasprescribed IMMEDIATE RELEASE NALTREXONE 0.5 mg in 2004 and sawimprovement by the following day slight, continued to see improvementand increased to 3 mg of the next 60 days, has more energy and the painlevel has decreased by 90% and cognitive ability and mood is better andno longer need to take anti-depressants.

Rheumatoid Arthritis

A 59 year old male diagnosed 5 years ago with RA was treated withMethotrexate 25 mg per week and Remicade 300 U every 6 weeks, thefatigue and pain continued, along with the inflammation and generalweakness. Sleep disturbed nightly due to pain in my shoulders and hips.Patient felt her life was not acceptable and none of theimmunosuppression drugs were helping. In 2007 patient started 4.5 mg ofImmediate release naltrexone at bedtime and within 7 days patientstooped all traditional RA medications. Within two weeks patient stoppedeven ibuprophen. Rheumatoid factor has gone from 127 to 66 in 4 monthsand has stayed stable. Fatigue is gone. Occasionally patient has painbut it is easily controlled with a normal dosage of ibuprophen.

A 63-year-old female, diagnosed with RA in 1999 stayed very active until2005 on a combination of Methotrexate and Prednisone but was havedifficulty maintaining her business due to fatigue and severe joint painwith deformity of her hands and elbows. Patient was told to increase herdoes and start a second immunomodulating drug. Patient no longer wantedto continue with immunosuppression drug or steroids due to the sideeffects. In 2008 patient started a new protocol which included dietarychanges, supplements, acupuncture, microcurrent therapy, toxicitytesting and treatment, Bio-identical hormones, adrenal support andthyroid started, Immediate release naltrexone started at 4.5 mg RA,discontinued the use of all other RA medication over a three weekperiod. 7 years later, still not on any other drugs, RA has notadvanced; she has no pain that can't be handled with aspirin.

The following references are herein incorporated by reference in theirentirety.

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What is claimed is:
 1. A method for treating or preventing autoimmuneand inflammatory diseases comprising administering to a mammal in needthereof an Immediate release pharmaceutical composition comprisingbetween about 0.01 mg and about 10.0 mg of naltrexone or apharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the amount of naltrexone is between about 1.0 mg and about 8.0mg.
 3. The method of claim 1, wherein the amount of naltrexone isbetween about 0.05 mg and about 6.0 mg.
 4. The method of claim 1,wherein the amount of naltrexone is between about 0.05 mg and about 4.5mg.
 5. The method of claim 1, wherein the autoimmune and inflammatorydiseases are chosen from the group consisting of allergic diseases,amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus,chronic rheumatoid arthritis, type I diabetes mellitus, inflammatorybowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn'sdisease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,autoimmune myositis, Wegener's granulomatosis, ichthyosis, Gravesophthalmopathy and asthma, bone marrow or organ transplant rejection orgraft-versus-host disease, transplantation of organs or tissue,graft-versus-host diseases brought about by transplantation, Hashimoto'sthyroiditis, systemic sclerosis, myasthenia gravis, uveitis, posterioruveitis, allergic encephalomyelitis, glomerulonephritis, post-infectiousautoimmune diseases including rheumatic fever and post-infectiousglomerulonephritis, inflammatory and hyperproliferative skin diseases,psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis,seborrhoeic dermatitis, lichen planus, pemphigus, epidermolysis bullosa,urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia,acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis,uveitis associated with Behcet's disease, keratitis, herpetic keratitis,conical cornea, dystrophia epithelialis comeae, corneal leukoma, ocularpemphigus, Mooren's ulcer, scleritis, Vogt-Koyanagi-Harada syndrome,sarcoidosis, pollen allergies, reversible obstructive airway disease,chronic obstructive pulmonary disorder (COPD), bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns, coeliac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, ulcerative colitis,migraine, rhinitis, eczema, interstitial nephritis, Goodpasture'ssyndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiplemyositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis,multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism,Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplasticanemia, idiopathic thrombocytopenic purpura, autoimmune hemolyticanemia, agranulocytosis, pernicious anemia, megaloblastic anemia,anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathicinterstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosisvulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, chroniclymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitissyndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener'sgranuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis, lesionsof gingiva, periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenesis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, partial liver resection,acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock,or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic cirrhosis, hepatic failure, fulminant hepatic failure,late-onset hepatic failure, “acute-on-chronic” liver failure,augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMVinfection, AIDS, trauma, Blephartis, and chronic bacterial infection. 6.The method of claim 5, wherein the autoimmune and inflammatory diseaseis Crohn's disease.
 7. The method of claim 1, wherein saidadministration is once in a 24 hour period.
 8. The method of claim 1,wherein said mammal is a human.
 9. The method of claim 1, wherein saidpharmaceutically acceptable salt is the hydrochloride salt.
 10. Themethod of claim 1, wherein said Immediate release composition releasesthe pharmaceutically acceptable salt of naltrexone completely withinabout 60 minutes.
 11. The method of claim 1, wherein said administrationis chosen from the group consisting of oral, sublingual, subcutaneous,intramuscular, intravenous, topical, local, intratracheal, intranasal,transdermal and rectal administration.
 12. The method of claim 1,wherein said Immediate release composition is in the form of a capsulesor tablet.
 13. The method of claim 1, wherein said Immediate releasecomposition is in the form of a rapidly dissolving film.